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  5. 胃癌FGFR2b过表达治疗进展与未来竞争格局分析

胃癌FGFR2b过表达治疗进展与未来竞争格局分析

深度研究Gin Gong发表于 2025年12月18日 22:255阅读
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发起深度研究

1. FGFR2b在胃癌中的生物学特性与作用机制

1.1 FGFR2b的分子结构与功能特征

成纤维细胞生长因子受体2b（FGFR2b，又称角质形成细胞生长因子受体, KGFR）是FGFR家族中的一个重要受体酪氨酸激酶亚型，主要在上皮细胞中表达1。FGFR家族是跨膜受体，通过细胞外的免疫球蛋白（Ig）样结构域与成纤维细胞生长因子（FGF）家族配体结合，并在细胞内通过酪氨酸激酶结构域进行信号传导2。FGFR2b特指FGFR2基因通过选择性剪接产生的IIIb剪接异构体，其细胞外配体结合区域的特异性决定了其对某些FGF配体（如FGF7、FGF10）具有更高的亲和力34。研究也表明FGFR2在胃癌中表达上调5。

FGFR2b的配体结合模式主要涉及其细胞外结构域与FGF配体形成二聚体，进而激活细胞内酪氨酸激酶结构域的自磷酸化。这一过程启动了一系列下游信号通路的级联反应。主要的下游信号通路包括：

  1. RAS-MAPK (RAF/MEK/ERK) 信号通路：FGFR2b激活后，通过适配蛋白Grb2/Sos募集并激活Ras蛋白，进而启动Raf-MEK-ERK激酶链。ERK1/2的活化最终导致细胞增殖、分化和存活相关基因的表达调控。
  2. PI3K-AKT (PI3K/AKT/mTOR) 信号通路：FGFR2b的激活也能募集PI3K，使其磷酸化并激活AKT。AKT是细胞生长、代谢、凋亡抑制的关键调控因子，其活化可进一步激活mTOR信号通路，促进蛋白质合成和细胞生长。研究表明，PI3K/Akt/mTOR信号通路在FGF7/FGFR2b诱导的血小板反应蛋白-1（THBS1）上调中起主导作用，进而促进胃癌细胞的侵袭和迁移6。此外，AKT信号传导在KGFR介导的角质形成细胞分化中也发挥作用1。
  3. PLCγ 信号通路：FGFR2b激活后也能磷酸化并激活磷脂酶Cγ（PLCγ），进而导致IP3和DAG的产生，影响细胞内钙离子水平和蛋白激酶C的活化，参与细胞的增殖和分化过程。然而，有研究表明，FGFR2b介导的角质形成细胞分化需要受体激酶活性，但不需要PLCγ介导的信号传导1。
  4. JNK 信号通路：Jun N-末端激酶（JNK）信号通路也被证明参与FGFR2b诱导的自噬和早期分化过程，表明其在调控细胞命运中的重要作用7。

在胃癌细胞中，FGFR2b的过表达或异常激活对肿瘤的发生发展具有多方面调控作用：

  • 细胞增殖：通过激活RAS-MAPK和PI3K-AKT通路，FGFR2b信号能显著促进胃癌细胞的增殖，导致肿瘤体积的快速增大。
  • 侵袭和迁移：FGFR2b信号的激活已被证明与胃癌细胞的侵袭和迁移能力增强有关，这主要是通过上调如THBS1等多种效应分子来实现的6。
  • 血管生成：尽管本节未直接提及FGFR2b在胃癌血管生成中的直接作用，但FGFR家族普遍参与血管生成过程。FGFs作为有效的促血管生成因子，通过与FGFRs结合来促进内皮细胞的增殖、迁移和形成管状结构。在肝再生过程中，FGF7/FGFR2b信号通路已被证明可促进肝细胞增殖3。
  • 细胞分化：KGFR（FGFR2b）在调节角质形成细胞的早期分化中起关键作用，其表达水平与分化标志物角蛋白1的水平呈正相关1。在胃癌中，FGFR2b的异常表达可能导致细胞分化异常，从而促进肿瘤恶性表型。

值得注意的是，FGFR2 C-末端区域的截短突变（FGFR2ΔE18）能够导致FGFR2的持续性激活，使其在没有配体结合的情况下也能发挥致癌作用，这提示了C-末端在抑制FGFR2激酶活性中的关键作用8。这种持续激活进一步强化了下游信号通路，加剧了肿瘤的进展。此外，有研究显示，在弥漫型胃癌（DGC）中，FGFR2的高表达与肿瘤侵袭深度、淋巴结转移和远处转移显著相关，并预示着更差的疾病特异性生存期9。FGFR2的基因扩增也与FGFR2b蛋白和mRNA的过表达密切相关，且与较差的总生存期相关10。这些证据共同表明FGFR2b在胃癌的生物学特性中扮演着核心角色。

1.2 胃癌中FGFR2b过表达的流行病学与异质性

FGFR2b过表达在胃癌（GC）中作为潜在的生物标志物和治疗靶点，其流行病学特征和异质性是理解其临床意义的关键。

FGFR2b过表达的检出率

多项研究评估了FGFR2b过表达在胃癌患者中的发生率，但结果因检测方法、定义标准和患者队列的差异而有所不同。

  • 高检出率：根据FORTITUDE-101 III期临床试验的预筛选数据，一项涵盖近3,800份肿瘤样本的大型评估报告指出，FGFR2b蛋白在晚期胃癌或胃食管结合部癌（GC/GEJC）患者中，以任意百分比肿瘤细胞（TC）显示中度至强（2+/3+）膜染色为标准，过表达率为 37.8%（1,428/3,782）。若进一步限定为≥10% TC具有2+/3+染色，则过表达率为 16.2% (612/3,782) 11。
  • 中低检出率：另一项回顾性队列研究评估了547名GC/GEJC患者，FGFR2b在任意2+/3+染色肿瘤细胞中的估计患病率为 15.4%（95% CI 12.4%-19.0%）。对于在研究启动后1.5年内收集样本的患者，这一比例更高，达到29.8% 12。此外，一项纳入1974例胃癌患者的研究显示，FGFR2b过表达的总体检出率为 4%，且通过免疫组化（IHC）检测的FGFR2b阳性与FGFR2基因扩增高度相关，所有IHC 2+和3+的病例均存在FGFR2扩增 13。在日本的一项大规模队列研究中，FGFR2基因强扩增（FGFR2:CEN10 >10）的发生率为2%（12/578），而FGFR2 mRNA高表达（score 4）的发生率为4%（29/718）14。
  • FGFR2b亚型特异性：FGFR2具有IIIb和IIIc两种亚型。一项针对562例胃癌患者的研究发现，FGFR2IIIb过表达率为 4.9%，而FGFR2IIIc过表达率仅为 0.7%。所有FGFR2IIIc阳性病例也同时FGFR2IIIb阳性，但不在同一癌细胞中 15。

这些数据表明，FGFR2b过表达在胃癌中并不少见，但其精确的检出率高度依赖于检测标准和方法学。

组织学分布

FGFR2b过表达在胃癌的不同组织学类型中存在一定的倾向性：

  • 弥漫型胃癌富集：一些研究表明，FGFR2b过表达在弥漫型胃癌（Lauren分类）中更为常见 1316。例如，有研究发现FGFR2b过表达在弥漫型胃癌中显著更频繁 13。在欧洲中部队列中，FGFR2阳性的弥漫型胃癌患者预后较差 16。
  • 低分化胃癌：FGFR2b的过表达与较低的肿瘤分级和肠型表型相关 16。CLDN18.2阳性与低分化组织学以及晚期pT和pN分期相关，而CLDN18.2与FGFR2b存在显著重叠，提示FGFR2b也可能与低分化胃癌相关 17。

肿瘤内/间异质性

胃癌中FGFR2b表达的异质性是一个显著的挑战，可能影响治疗决策和患者选择：

  • 瘤内异质性（Intratumoral Heterogeneity, ITH）：
    • IHC染色不均一：FGFR2b蛋白表达在肿瘤内部表现出显著的异质性，许多FGFR2阳性胃癌病例显示出不同的染色强度组合，包括弱、中、强染色在不同区域的混杂分布 16。一项研究观察到55.5%的病例存在FGFR2b蛋白过表达的瘤内异质性，而FGFR2 mRNA过表达的瘤内异质性更高，达到85.7% 10。
    • 基因扩增异质性：FGFR2基因扩增也表现出高度的瘤内异质性。一项针对893例上消化道腺癌（包括胃癌）的研究发现，93%的胃癌病例显示出异质性扩增，这意味着FGFR2扩增克隆在肿瘤内部分布不均 18。另一项研究也指出FGFR2扩增存在显著的瘤内异质性，且扩增/多倍体与FGFR2 mRNA表达之间的一致性差 19。
  • 肿瘤间异质性（Intertumoral Heterogeneity）：
    • 原发灶与转移灶不一致：FGFR2b表达在原发肿瘤和其匹配的转移淋巴结之间存在不一致性。研究显示，55.5%的病例在原发灶和转移淋巴结之间FGFR2b蛋白表达不一致，而FGFR2 mRNA表达的不一致性为28.6% 10。在另一项比较原发灶和腹膜转移灶中FGFR2b表达的研究中，仅有1例病例在原发灶和转移灶中均FGFR2b阳性，表明空间异质性显著 20。FGFR2b在转移性胃癌中的阳性率和阳性肿瘤细胞百分比显著高于原发性胃癌（8% vs 3%，75% vs 47%；p<0.001）13。
    • 活检与手术标本：一项研究发现，配对活检和手术样本之间的不一致性在FGFR2b过表达中达到20.0%，在FGFR2b阳性中达到40.0%，进一步强调了瘤内异质性的普遍性 21。

这些异质性特征对FGFR2b作为生物标志物的检测提出了挑战，尤其是在活检样本量有限或存在多个病灶的情况下。精准检测需要更全面地评估肿瘤FGFR2b状态，可能包括多点活检或综合原发灶与转移灶的检测结果。

1.3 FGFR2b与胃癌预后及分子分型的关联

FGFR2b在胃癌中的过表达不仅是治疗靶点，其与患者的预后以及胃癌的分子分型也存在密切关联，为精准医疗提供了重要信息。

FGFR2b过表达与患者生存预后的关联

多项研究探讨了FGFR2b过表达与胃癌患者预后之间的关系，但结果不尽一致，可能与研究人群、检测方法以及FGFR2b过表达的定义标准等因素有关。

  • 不良预后指示：一些研究表明，FGFR2b过表达与胃癌患者的较差预后相关。例如，一项研究发现在接受氟嘧啶和铂类化疗的晚期胃癌患者中，FGFR2基因扩增组的总体生存期（OS）显著短于无扩增组（风险比 [HR]=1.92, 95% CI: 1.13-3.26, p=0.015），尽管多变量分析显示其并非独立的预后因素 22。另一项研究则指出，高水平FGFR2扩增（拷贝数变异 >30）的胃癌患者，其中位无进展生存期（PFS）和中位总生存期（OS）均显著差于低扩增组（PFS: 3.2 vs 4.8个月, HR 2.08, p=0.042; OS: 10.1 vs 26.3个月, HR 2.99, p=0.040）23。这表明，FGFR2b的高水平异常可能预示着更具侵袭性的肿瘤生物学行为和对传统化疗的较低响应。此外，有研究指出FGFR2在弥漫型胃癌中的过表达与其侵袭性表型和较差的预后相关 24。
  • 中性或积极预后指示：然而，也有研究显示FGFR2b过表达与预后无显著关联，或者在特定治疗背景下显示出积极趋势。一项研究评估了接受一线纳武利尤单抗联合化疗的胃癌患者，发现FGFR2b过表达和低表达的患者与FGFR2b阴性患者相比，呈现出有利的生存趋势，这在单纯化疗组中未观察到 21。这可能提示FGFR2b在免疫检查点抑制剂联合化疗中具有预测治疗应答的潜力，而不仅仅是独立的预后标志物。
  • FGFR2亚型异构体的影响：值得注意的是，FGFR2的不同剪接异构体对预后可能产生差异影响。FGFR2-IIIc高比例表达与显著较短的总生存期相关（中位OS 9.59 vs 16.0个月，HR 2.08），并被证实是独立的预后不良预测因子 25。这强调了在评估FGFR2b预后价值时，需要更精细地区分FGFR2的不同亚型表达状态。

FGFR2b在胃癌分子分型中的定位与临床意义

胃癌的分子分型为理解其异质性提供了框架，并有助于指导个体化治疗。FGFR2b过表达在这些分型中占据一定位置。

  • TCGA分类中的定位：根据The Cancer Genome Atlas (TCGA) 的分子分型，胃癌被分为四类：染色体不稳定型 (CIN)、基因组稳定型 (GS)、微卫星不稳定型 (MSI) 和爱泼斯坦-巴尔病毒 (EBV) 阳性型。FGFR2通路在胃癌发病机制中扮演关键角色，1.2%–9%的胃癌患者存在FGFR2扩增，这有助于深入理解胃癌的分子异质性 26。
  • 与其他生物标志物的关系：FGFR2b的过表达可能与其他致癌通路如HER2和PD-L1的表达存在一定的互斥或共存关系。了解这些关系有助于更精准地筛选患者并设计联合治疗方案。例如，一项网络荟萃分析指出，在大多数现有研究中，HER2阳性患者被排除在外，这提示FGFR2b靶向治疗可能主要针对HER2阴性患者群体 27。FGFR2b与CLDN18.2均是胃癌中新兴的生物标志物，它们的共表达模式和对治疗的指导作用仍在探索中，可能为未来的联合治疗策略提供依据 28。
  • 生物标志物富集：FIGHT研究的亚组分析显示，对于FGFR2b在≥10%肿瘤细胞中表达的患者，贝马珠单抗（bemarituzumab）联合mFOLFOX6化疗方案的治疗效果更为显著 29。这表明通过更严格的生物标志物筛选标准，可以更好地富集获益人群，进一步提升治疗效果。

综合来看，FGFR2b过表达在胃癌中可能预示不良预后，尤其是在存在高水平基因扩增时。然而，其在特定治疗（如免疫联合化疗）背景下可能具有预测应答的价值。未来，将FGFR2b纳入胃癌多维度分子分型体系，结合FGFR2不同异构体状态、与其他生物标志物的共表达情况，将有助于更精准地指导临床实践和药物开发。

2. FGFR2b靶向治疗的临床进展与关键试验

2.1 单克隆抗体类药物：以bemarituzumab为核心

Bemarituzumab (FPA144) 是一种人源化、去岩藻糖基化的免疫球蛋白G1（IgG1）单克隆抗体，其设计旨在特异性靶向成纤维细胞生长因子受体2b（FGFR2b）。作为FGFR2b靶向治疗领域的“首创”（first-in-class）药物，Bemarituzumab通过两种主要机制发挥抗肿瘤作用：抑制FGFR2b信号通路和增强抗体依赖性细胞介导的细胞毒性（ADCC）30。

作用机制

  1. 抑制FGFR2b信号：Bemarituzumab能够有效结合FGFR2b受体，阻断其与配体（如FGFs）的结合，从而抑制由FGFR2b异常激活驱动的下游信号通路（如RAS-MAPK和PI3K-AKT），进而抑制肿瘤细胞的增殖、存活和转移30。体外研究显示，Bemarituzumab能以亚纳摩尔级亲和力结合FGFR2b受体，并浓度依赖性地抑制FGFR2磷酸化和SNU-16胃癌细胞的增殖30。
  2. 增强ADCC效应：Bemarituzumab经过“去岩藻糖基化”（afucosylated）修饰，相较于其岩藻糖基化版本，其对人Fcγ受体IIIa的结合亲和力增强了20多倍30。这种增强的结合能力显著提高了自然杀伤（NK）细胞介导的ADCC效应，从而有效杀伤FGFR2b过表达的肿瘤细胞30。临床前研究表明，Bemarituzumab在体内能通过抑制FGFR2b通路和/或ADCC效应来抑制肿瘤生长30。

FIGHT系列试验的疗效数据

Bemarituzumab在针对FGFR2b过表达、HER2阴性胃癌或胃食管结合部腺癌（GC/GEJC）的FIGHT II期临床试验（NCT03694522）中取得了令人鼓舞的结果，奠定了其后续III期试验的基础313233。

  • FIGHT II期试验设计：该试验是一项随机、双盲、安慰剂对照的II期研究，旨在评估Bemarituzumab联合mFOLFOX6（改良的5-氟尿嘧啶、亚叶酸钙和奥沙利铂）化疗方案作为晚期GC/GEJC一线治疗的疗效和安全性3132。患者按照1:1的比例随机分入Bemarituzumab+mFOLFOX6组或安慰剂+mFOLFOX6组。Bemarituzumab的给药方案为每两周15 mg/kg，并在第1周期第8天额外给予7.5 mg/kg剂量31。主要终点是研究者评估的无进展生存期（PFS），次要终点包括总生存期（OS）、客观缓解率（ORR）和安全性31。
  • 疗效结果：
    • PFS：在中位随访10.9个月时，Bemarituzumab+mFOLFOX6组的中位PFS为9.5个月（95% CI 7.3-12.9），而安慰剂+mFOLFOX6组为7.4个月（95% CI 5.8-8.4）。虽然在整个意向治疗（ITT）人群中，PFS的风险比（HR）为0.68（95% CI 0.44-1.04; p=0.073），未达到统计学显著性，但表现出有前景的临床疗效趋势32。
    • OS：在中位随访24个月后的最终分析显示，Bemarituzumab+mFOLFOX6组的中位OS为19.2个月（95% CI 13.6-24.2），而安慰剂+mFOLFOX6组为13.5个月（95% CI 9.3-15.9），HR为0.77（95% CI 0.52-1.14）31。
    • 生物标志物富集：更值得关注的是，在FGFR2b过表达≥10%肿瘤细胞的患者亚组中，疗效更为显著。在该亚组中，Bemarituzumab+mFOLFOX6组的PFS HR为0.43（95% CI 0.26-0.73），OS HR为0.52（95% CI 0.31-0.85），表明Bemarituzumab在高度FGFR2b过表达的患者中具有更优异的治疗效果31。这一发现强调了精准筛选患者的重要性。
  • 正在进行的III期试验：基于FIGHT II期试验的积极结果，两项确证性III期临床试验正在进行中，分别为FORTITUDE-101 (NCT05052801) 和FORTITUDE-102 (NCT05111626)，以进一步评估Bemarituzumab+mFOLFOX6在FGFR2b过表达晚期GC/GEJC患者中的疗效和安全性313234。FORTITUDE-101研究计划入组约3700名患者进行FGFR2b过表达筛选，其中大约16%的患者预计为FGFR2b ≥10% TC 2+/3+阳性11。

安全性特征

Bemarituzumab的安全性在FIGHT II期试验中得到了评估。

  • 常见不良事件：Bemarituzumab组与安慰剂组相比，3级或更高级别的常见不良事件包括中性粒细胞计数降低（30% vs 35%）、角膜疾病（24% vs 0%）、中性粒细胞减少症（13% vs 9%）、口腔炎（9% vs 1%）和贫血（8% vs 13%）32。
  • 角膜毒性：Bemarituzumab治疗组中，各种级别的角膜事件（特殊关注的不良事件）发生率较高，达到67%，而安慰剂组为10%32。其中，3级角膜事件仅在Bemarituzumab组中发生，比例为24%32。这些角膜相关不良事件通常表现为干眼症、角膜炎或视力模糊，但多数可控，且通常通过局部用药或剂量调整解决。
  • 治疗相关死亡：Bemarituzumab组有3例治疗相关死亡（2例死于脓毒症，1例死于肺炎），安慰剂组无32。

总体而言，Bemarituzumab联合mFOLFOX6治疗方案在FGFR2b过表达晚期胃癌或胃食管结合部腺癌患者中显示出有前景的疗效，尤其是在高表达患者亚组。其独特的ADCC增强机制和信号抑制作用，使其成为精准治疗该类患者的重要候选药物。尽管存在角膜毒性等不良反应，但考虑到其潜在的生存获益，Bemarituzumab的市场前景广阔。

2.2 小分子抑制剂的探索与挑战

小分子酪氨酸激酶抑制剂（FGFR-TKI）通过可逆或不可逆地竞争性结合FGFR的ATP结合位点，从而抑制FGFR的酪氨酸激酶活性，阻断下游信号传导。在胃癌中，针对FGFR2基因扩增或过表达患者的小分子抑制剂研发取得了积极进展，但临床尝试也面临疗效局限性和毒性管理的挑战。

AZD4547在胃癌中的临床尝试

AZD4547是一种口服、选择性FGFR1、FGFR2和FGFR3抑制剂。在临床前研究中，AZD4547已显示出对FGFR2扩增的胃癌细胞株的有效抑制作用。

  • 疗效局限性：尽管AZD4547在临床前表现良好，但在胃癌患者中的临床试验结果却不尽如人意。一项II期临床研究评估了AZD4547单药治疗或联合化疗（紫杉醇或多西他赛）在FGFR2扩增的晚期胃癌患者中的疗效。结果显示，单药治疗的客观缓解率（ORR）较低，且联合化疗的获益也不显著。导致这种疗效局限性的原因可能与肿瘤的复杂性以及可能存在的原发性或获得性耐药机制有关。例如，有研究发现，多种受体酪氨酸激酶（RTK）如EGFR、HER3和MET的激活，可导致FGFR2扩增的胃癌细胞对AZD4547产生低敏感性。当这些RTK被抑制时，AZD4547的疗效得以恢复，提示联合抑制可能是一个方向 35。
  • 剂量限制毒性（DLT）：AZD4547最常见的剂量限制性毒性是高磷血症，这在所有FGFR抑制剂中都较为常见。其他不良反应还包括视力障碍、口腔炎、腹泻等。这些毒性反应限制了AZD4547的给药剂量和长期使用，影响了其临床应用的潜力。

futibatinib在胃癌中的临床尝试

futibatinib（TAS-120）是一种口服、不可逆、选择性的泛FGFR1-4抑制剂。与AZD4547等可逆抑制剂不同，futibatinib通过与FGFR的半胱氨酸残基形成共价键，实现持久的酶抑制，旨在克服传统FGFR-TKI的耐药性问题。

  • 疗效数据：一项开放标签的II期临床研究评估了futibatinib在FGFR2扩增的胃癌或胃食管结合部癌患者中的疗效和安全性 36。
    • 客观缓解率（ORR）：独立中心评估的ORR为17.9%，其中5名患者达到部分缓解（PR），中位缓解持续时间（DoR）为3.9个月 36。另有9名患者疾病稳定，疾病控制率（DCR）为50.0% 36。这一ORR相对较低，表明futibatinib单药在FGFR2扩增胃癌中的抗肿瘤活性有限。
    • 生存数据：独立中心评估的中位无进展生存期（PFS）为2.9个月，中位总生存期（OS）为5.9个月 36。这些生存数据提示futibatinib单药治疗的临床获益仍需进一步提升。
  • 安全性特征：futibatinib的安全性概况与既往FGFR抑制剂报告一致，最常见的治疗相关不良事件（任意级别）是高磷血症（89.3%），其次是食欲下降（32.1%）和天冬氨酸转氨酶升高（21.4%） 36。仅有1名（3.6%）患者因不良事件而中止治疗，表明其总体耐受性尚可 36。尽管高磷血症发生率高，但通常可控，且严重程度较低。

小分子FGFR-TKI面临的共同挑战

  1. ORR偏低：与单克隆抗体bemarituzumab在特定富集人群中展现的较好疗效相比，小分子FGFR-TKI在胃癌中的单药ORR普遍偏低。这可能与FGFR2扩增的异质性、旁路激活、或肿瘤微环境的复杂性有关。
  2. 剂量限制毒性：高磷血症是所有FGFR抑制剂的“靶点效应”毒性，因为它抑制了FGFR介导的磷酸调节。此外，角膜毒性、皮肤毒性、口腔炎等也是常见的脱靶或靶向相关副作用。这些毒性可能导致患者依从性下降，或需要剂量调整甚至停药，从而影响治疗效果。
  3. 原发性和获得性耐药：小分子FGFR-TKI治疗后，肿瘤细胞可能通过多种机制产生耐药性，包括FGFR2基因的二次突变（如“看门人”突变V555M） 37、旁路信号通路的激活（如IGF-1R、FGFR1激活）或肿瘤微环境的适应性改变。例如，AZD4547耐药株可通过脂质代谢紊乱和CHAC1介导的铁死亡抑制来逃避治疗 38。
  4. 患者选择不足：目前对于小分子FGFR-TKI治疗的最佳受益人群筛选尚不明确。单纯的FGFR2扩增或过表达可能不足以预测疗效，需要更深入的生物标志物研究来识别对治疗更敏感的患者亚群。

总而言之，尽管小分子FGFR-TKI在FGFR2异常的胃癌中展现了一定的抗肿瘤活性，但其单药疗效有限，且面临耐药性和毒性管理等挑战。未来的发展方向可能包括与其他靶向药物、化疗或免疫疗法的联合应用，以及开发更具选择性、更少毒性的新型抑制剂，并结合更精准的患者筛选策略。

2.3 联合治疗策略的突破：化疗、免疫与多靶点协同

为了克服单药治疗的局限性并提高胃癌患者的疗效，联合治疗策略，包括靶向治疗与化疗、免疫疗法以及多靶点抑制剂的协同应用，已成为当前研究的热点。

化疗联合方案的协同增效机制

靶向FGFR2b的药物与传统化疗药物的联合应用，旨在通过多通路协同作用，更有效地抑制肿瘤生长。以bemarituzumab联合mFOLFOX6为例，其协同增效机制主要体现在以下几个方面：

  1. FGFR2b信号抑制与细胞周期阻滞：Bemarituzumab通过阻断FGFR2b信号，抑制肿瘤细胞的增殖、存活和血管生成。化疗药物如5-氟尿嘧啶和奥沙利铂则通过损伤DNA或抑制DNA合成，诱导细胞周期阻滞和细胞凋亡。两者结合，Bemarituzumab抑制了FGFR2b通路驱动的细胞生长信号，使肿瘤细胞对化疗诱导的细胞损伤更为敏感，从而增强化疗药物的细胞毒性。
  2. 增强ADCC效应：Bemarituzumab作为去岩藻糖基化抗体，能通过增强ADCC效应直接杀伤FGFR2b高表达的肿瘤细胞。化疗可能会诱导肿瘤细胞表面表达更多的FGFR2b，或者通过释放损伤相关分子模式（DAMPs）激活免疫细胞，从而进一步增强Bemarituzumab介导的ADCC效应，形成免疫-化疗协同杀伤。
  3. 肿瘤微环境重塑：化疗和FGFR2b抑制剂都可能对肿瘤微环境产生影响。例如，化疗可以减少肿瘤负荷，改善肿瘤内部的氧合状态；FGFR2b信号抑制可能影响肿瘤血管生成和基质细胞功能。这种微环境的改变可能进一步优化化疗药物的递送，或促进免疫细胞浸润，从而增强联合治疗的整体效果。
  4. 克服潜在耐药机制：虽然Bemarituzumab主要作用于FGFR2b，但化疗药物的非特异性细胞毒性可以弥补靶向治疗可能遇到的旁路激活或肿瘤异质性导致的耐药问题，从而实现更广泛的抗肿瘤效果。FIGHT II期临床试验已初步证实了Bemarituzumab联合mFOLFOX6方案的临床获益，尤其是在FGFR2b高表达患者中表现出显著的PFS和OS改善 31。在东亚患者亚组中，Bemarituzumab联合mFOLFOX6治疗使中位PFS延长至12.9个月，中位OS延长至24.7个月，相较于安慰剂组有显著提升 29。这些数据有力支持了靶向治疗与化疗的协同增效潜力。

免疫联合（如nivolumab+化疗）的疗效数据及PD-L1共表达的潜在价值

免疫检查点抑制剂（ICIs）的出现为胃癌治疗带来了革命性的变化。将ICIs与化疗联合，并进一步探索与FGFR2b靶向治疗的结合，是未来的重要方向。

  1. NIVOFGFR2研究的疗效数据：NIVOFGFR2是一项前瞻性II期临床研究，旨在评估nivolumab（一种抗PD-1抗体）联合化疗（CAPOX：卡培他滨+奥沙利铂）在FGFR2和PD-L1共表达的转移性胃癌患者中的疗效和安全性。这项研究入组了23名先前未经治疗、HER2阴性、PD-L1阳性且FGFR2阳性的转移性胃癌患者。研究结果显示：

    • PFS和OS：中位随访17.3个月时，1年PFS率为30.4%，中位PFS为6.0个月（95% CI, 4.3-7.7）。中位OS为15.1个月（95% CI, 13.2-16.8）39。
    • ORR：客观缓解率为21.7%，其中1例完全缓解，4例部分缓解 39。
    • 安全性：3级或更高级别的治疗相关不良事件发生率为34.8%，主要与化疗相关，未发生治疗相关死亡 39。
    • 解读：尽管该研究未达到改善1年PFS率的主要终点，但它为FGFR2和PD-L1共表达胃癌患者联合免疫治疗的潜力提供了有价值的见解 39。研究提示，在这一特定亚群中，免疫联合化疗可能提供一定获益，但需要进一步优化患者选择和治疗方案。

  2. PD-L1共表达的潜在价值：PD-L1表达通常被视为免疫检查点抑制剂疗效的预测生物标志物。在FGFR2b过表达的胃癌中，PD-L1的共表达可能具有多重临床意义：

    • 预测免疫治疗敏感性：PD-L1阳性与ICIs的更好疗效相关，这表明FGFR2b/PD-L1双阳性患者可能对免疫联合治疗有更好的响应。FGFR2通路激活与肿瘤微环境中的免疫抑制可能存在关联，理论上，抑制FGFR2通路可能有助于逆转免疫抑制，从而增强PD-1/PD-L1阻断的效果。
    • 指导联合策略：在NIVOFGFR2研究中，筛选PD-L1阳性患者入组，旨在富集对免疫治疗更敏感的群体 39。未来的研究可以探索FGFR2b靶向治疗、化疗和免疫治疗的“三联”方案，尤其是在PD-L1高表达且FGFR2b过表达的患者中，以期实现更强的协同效应。例如，FGFR抑制可能通过减少肿瘤相关成纤维细胞（CAFs）和免疫抑制细胞的浸润来改善肿瘤微环境，从而增强免疫治疗的效果。

  3. 多靶点协同的未来方向：鉴于胃癌的高度异质性和复杂性，单一靶点抑制往往面临耐药挑战。因此，开发多靶点协同策略至关重要。这可能包括：

    • FGFR2b与其他RTK的联合抑制：如前所述，其他RTK的激活可导致对FGFR2抑制剂的耐药。因此，联合抑制FGFR2b与EGFR、HER3或MET等RTK可能是一个有效的策略。
    • FGFR2b与CLDN18.2的联合靶向：CLDN18.2是一种在胃癌中发现的治疗靶点，zolbetuximab已显示出其在Claudin 18.2过表达肿瘤中的疗效 40。探索同时靶向这些不同分子或结合其他靶向药物的策略可能带来更广泛的临床获益。
    • 新型抗体偶联药物（ADCs）：将FGFR2b靶向抗体与细胞毒性药物偶联，可以实现精准递送化疗药物，减少全身毒性，并克服部分耐药机制。

总之，联合治疗策略在胃癌FGFR2b过表达患者中展现出巨大潜力。通过精准选择患者、优化药物组合及探索多靶点协同机制，有望显著改善胃癌的治疗效果。

3. FGFR2b靶向治疗的耐药机制与应对策略

3.1 原发性耐药的分子基础

尽管FGFR2b靶向治疗在胃癌中展现出潜力，但原发性耐药（Primary Resistance）是限制其疗效的重大挑战。原发性耐药指的是肿瘤细胞在接触FGFR2b抑制剂之前或首次接触时即不敏感。这种耐药性的分子基础复杂多样，涉及肿瘤微环境的适应性改变以及肿瘤细胞内在的分子机制。

肿瘤微环境对FGFR2b信号持续激活的影响

肿瘤微环境（Tumor Microenvironment, TME）是肿瘤细胞赖以生存和发展的重要生态系统，其组成和动态变化可显著影响肿瘤对治疗的响应。在FGFR2b靶向治疗中，TME可能通过多种途径导致原发性耐药：

  1. 脂质代谢异常：胃癌细胞，特别是那些对FGFR-TKI耐药的细胞，常表现出异常的脂质代谢。研究发现，在FGFR-TKI耐药的胃癌细胞中，胆固醇积累显著，且硬脂酸（SA）的摄取减少 38。胆固醇作为细胞膜的重要组分，其异常积累可能影响膜蛋白的结构和功能，包括FGFR2b的定位和活性，或通过调节下游信号通路来抵抗治疗。这种脂质稳态的失调不仅可以下调CHAC1介导的铁死亡，而且直接参与了FGFR-TKI耐药的形成 38。
  2. ecDNA动态与FGFR2高表达：染色体外环状DNA（extrachromosomal DNA, ecDNA）是癌细胞中常见的基因扩增形式，能够携带致癌基因，并赋予肿瘤细胞强大的异质性和适应性。研究表明，在某些FGFR2b过表达的胃癌中，FGFR2基因可能以ecDNA形式存在。ecDNA的动态变化和高拷贝数可以导致FGFR2基因的高表达，从而产生大量的FGFR2b蛋白。当FGFR2b表达水平极高时，即使FGFR2b抑制剂能够结合部分受体，剩余的未被抑制的受体仍足以维持下游信号通路的激活，从而导致原发性耐药。此外，ecDNA的存在也可能增加基因组不稳定性，促进其他耐药相关基因的产生或放大。
  3. 旁路激活：TME中的细胞因子、生长因子或其他信号分子可能激活FGFR2b下游的旁路信号通路，即使FGFR2b本身被抑制，这些旁路通路仍能驱动肿瘤细胞的增殖和存活。例如，多种受体酪氨酸激酶（RTK）如EGFR、HER3和MET的激活可导致FGFR2扩增的胃癌细胞对AZD4547产生低敏感性。当这些RTK被抑制时，AZD4547的疗效得以恢复，提示这些旁路通路在原发性耐药中发挥作用 。

CHAC1下调抑制铁死亡

铁死亡（Ferroptosis）是一种由铁离子依赖性脂质过氧化驱动的程序性细胞死亡形式，与多种癌症的发生发展及治疗敏感性密切相关。

  • FGFR-TKI诱导铁死亡：有研究表明，FGFR-TKI，例如AZD4547，能够在敏感的胃癌细胞中诱导铁死亡 38。这意味着铁死亡是FGFR-TKI发挥抗肿瘤作用的重要机制之一。
  • CHAC1在耐药中的作用：谷胱甘肽特异性降解酶CHAC1是铁死亡的关键调节因子。它通过降解谷胱甘肽（GSH）来促进铁死亡的发生。在FGFR-TKI耐药的胃癌细胞中，CHAC1的表达显著下调，导致细胞对铁死亡的敏感性降低 38。当CHAC1表达下调时，GSH水平维持较高，从而抑制了脂质过氧化，使肿瘤细胞能够逃避FGFR-TKI诱导的铁死亡，进而产生原发性耐药。
  • 脂质稳态与CHAC1：进一步的研究发现，上述提到的脂质代谢异常，特别是胆固醇的积累，与CHAC1的下调存在关联 38。胆固醇的积累可能通过某种机制影响CHAC1的表达或活性，从而协同抑制铁死亡通路，共同促进FGFR-TKI的原发性耐药。

综上所述，原发性耐药是胃癌FGFR2b靶向治疗面临的复杂问题，其根源在于肿瘤细胞内在的分子机制（如ecDNA导致的FGFR2高表达、CHAC1下调抑制铁死亡）与肿瘤微环境的适应性改变（如脂质代谢异常、旁路信号激活）之间的相互作用。深入理解这些机制对于开发有效的耐药应对策略至关重要。

3.2 获得性耐药的进化路径

获得性耐药（Acquired Resistance）是指肿瘤在最初对FGFR2b靶向治疗敏感并产生响应后，经过一段时间的治疗，肿瘤细胞重新获得生长优势，导致疾病进展。这种现象是靶向治疗的普遍挑战，其背后是复杂的分子进化过程，即在药物选择压力下，耐药克隆的富集和扩增。

长期治疗后耐药克隆的选择压力

FGFR2b抑制剂的持续暴露对肿瘤细胞施加了巨大的选择压力。在此压力下，那些能够规避药物作用或激活替代生存通路的肿瘤细胞克隆会逐渐被筛选出来并获得生长优势。这些耐药克隆通过多种机制实现对药物的抵抗，包括靶点本身的改变、下游或旁路信号通路的激活，以及肿瘤细胞表型的转变。

FGFR2二次突变

FGFR2基因本身的二次突变是获得性耐药的一种常见机制，这些突变通常发生在FGFR2的激酶结构域，影响药物与靶点的结合：

  1. 看门人突变：最常见的二次突变之一是FGFR2的“看门人”（gatekeeper）残基突变。例如，FGFR2 V565F突变已被证明会导致对现有FGFR抑制剂的显著耐药 4142。在胆管癌患者中，接受泛FGFR抑制剂INCB054828治疗后，通过快速研究性尸检发现了一例FGFR2 N549H突变，导致对INCB054828的抗性增加150倍，并对其他选择性FGFR抑制剂也产生交叉耐药 42。这些突变改变了药物结合口袋的形状，降低了抑制剂的结合亲和力，使其失去抑制作用。
  2. 其他激酶结构域突变：除了看门人突变，FGFR2激酶结构域的其他位点突变也可能引起耐药。例如，新型共价FGFR抑制剂KIN-3248已被证明能有效克服多种FGFR2激酶结构域突变，包括V565F看门人突变，这表明针对这些耐药突变的新一代抑制剂正在开发中 41。

旁路激活

即使FGFR2本身未发生突变，肿瘤细胞也可能通过激活其他信号通路来绕过FGFR2抑制：

  1. 其他受体酪氨酸激酶（RTK）的激活：

    • EphB3：在AZD4547耐药的胃癌细胞株SNU-16R中，发现EphB3的磷酸化上调 43。EphB3的激活通过Ras-ERK1/2通路进一步激活mTOR，从而驱动细胞增殖和存活。使用EphB3的酪氨酸激酶抑制剂可逆转AZD4547的耐药性，抑制细胞增殖和诱导凋亡 43。
    • MET、HER3、EGFR：多项研究指出，MET、HER3和EGFR等RTK的激活可以作为FGFR2抑制剂的旁路激活机制，导致对FGFR2抑制剂的低敏感性 3544。当联合抑制这些旁路RTK时，可以恢复对FGFR2抑制剂的敏感性，表明联合治疗策略的潜力 35。在AZD4547耐药的SNU-16R细胞中，也观察到N-cadherin、vimentin、Snail、MMP-2和MMP-9的上调以及E-cadherin的下调，提示发生了上皮-间充质转化（EMT），而EphB3抑制剂可抑制这种EMT进程 43。
    • IGF-1R和FGFR1：在胃肠道间质瘤（GIST）中，尽管FGFR2抑制剂LY2874455最初有效，但获得性耐药可通过FGFR2-ACSL5融合的出现而发生 45。在FGFR2扩增的胃癌中，通过组学分析耐药细胞模型，发现IGF-1R和FGFR1的激活是导致对FGFR2抑制剂耐药的关键驱动通路。这些旁路通路的激活提供了替代的增殖和生存信号，使肿瘤细胞能够在FGFR2被抑制的情况下继续生长 46。

  2. 基因融合：耐药机制还可以涉及FGFR2与其他基因的融合。例如，在AZD4547耐药的SNU-16胃癌细胞中，发现了一种获得性JHDM1D-BRAF融合基因 47。该融合基因导致BRAF的活化，进而激活MAPK通路，使肿瘤细胞对FGFR抑制剂产生耐药性 47。有趣的是，JHDM1D-BRAF融合基因缺乏RAS结合域，但其二聚化能力增强，提示RAF二聚体抑制剂或MEK抑制剂可能有效对抗这种耐药机制 47。

耐药细胞模型的组学分析

为了深入理解获得性耐药的分子基础，研究人员常利用体外建立的耐药细胞模型和患者来源的肿瘤模型进行组学分析。例如，通过长期暴露于FGFR抑制剂（如AZD4547）来诱导胃癌细胞株（如SNU-16）产生耐药性，然后对耐药细胞进行基因组学、转录组学和蛋白质组学分析。

  • SNU-16R模型：以SNU-16细胞建立的AZD4547耐药株（SNU-16R）的组学分析揭示了EphB3磷酸化的上调和Ras-ERK1/2-mTOR通路的激活 43。
  • 染色体7q34区域扩增和JHDM1D-BRAF融合：在AZD4547耐药的SNU-16克隆中，比较基因组杂交分析发现染色体7q34区域扩增，并进一步鉴定出JHDM1D-BRAF融合基因，通过MAPK通路介导耐药 47。
  • FGFR2-ACSL5融合：在对LY2874455产生获得性耐药的FGFR2扩增胃癌患者来源细胞系中，RNA测序发现了一种新型的FGFR2-ACSL5融合基因 45。

这些组学研究不仅揭示了耐药的关键驱动通路，也为开发针对耐药机制的新型治疗策略提供了理论依据。理解这些获得性耐药的进化路径对于设计更有效的联合治疗方案和序贯治疗策略至关重要。

3.3 克服耐药的潜在策略

面对FGFR2b靶向治疗的原发性及获得性耐药挑战，开发有效的应对策略至关重要。这些策略主要集中在针对耐药机制的干预，包括靶向复制应激、纠正代谢异常以及利用新型降解技术。

CHK1抑制剂（BBI-2779）靶向ecDNA复制应激

染色体外环状DNA（ecDNA）是许多癌症中常见的致癌基因扩增形式，与肿瘤的治疗抵抗性、快速基因组进化和不良预后密切相关 48。在胃癌模型中，ecDNA上扩增的FGFR2可介导对泛FGFR抑制剂infigratinib的获得性耐药 48。ecDNA上的基因具有高水平的转录活性，这导致了严重的转录-复制冲突（transcription-replication conflict, TRC）和复制应激 48。

  • ecDNA与复制应激：ecDNA上普遍存在广泛的RNA转录和相关的单链DNA，与染色体基因座相比，这会导致过度的TRC和复制应激 48。ecDNA上的核苷酸掺入速度明显较慢，且复制应激显著高于ecDNA阳性肿瘤，无论癌症类型或致癌基因如何 48。DNA损伤修复的介质pRPA2-S33在ecDNA上表现出转录依赖性的升高定位，伴随着DNA双链断裂的增加和S期检查点激酶CHK1的激活 48。
  • CHK1抑制剂的作用机制：Chk1（Checkpoint Kinase 1）是细胞周期检查点激酶，在DNA损伤和复制应激响应中发挥关键作用。基因或药理学抑制CHK1会导致ecDNA阳性肿瘤细胞发生广泛且优先的细胞死亡 48。
  • BBI-2779的潜力：BBI-2779是一种高选择性、高效且生物利用度高的口服CHK1抑制剂，已被证明能优先杀伤ecDNA阳性的肿瘤细胞 48。在携带FGFR2ecDNA扩增的胃癌模型中，BBI-2779能够抑制肿瘤生长，并阻止泛FGFR抑制剂infigratinib引发的ecDNA介导的获得性耐药，从而实现强效且持续的肿瘤消退 48。这表明，通过增强TRC来靶向ecDNA阳性癌症，利用“过度合成致死性”（synthetic lethality of excess），为FGFR2b过表达胃癌的耐药管理提供了新的治疗策略 48。

胆固醇合成抑制剂逆转脂质代谢异常

如前所述，FGFR-TKI耐药的胃癌细胞常伴随异常的脂质代谢，特别是胆固醇的积累，并导致CHAC1下调抑制铁死亡，从而促进耐药的发生。针对这一机制，胆固醇合成抑制剂有望逆转耐药。

  • 脂质代谢在耐药中的作用：FGFR-TKI敏感的胃癌细胞在用FGFR-TKI处理后会经历铁死亡，而耐药细胞则通过多种途径抑制铁死亡，其中之一是下调CHAC1并伴随脂质代谢紊乱，包括胆固醇积累和硬脂酸（SA）摄取减少。
  • 胆固醇合成抑制剂的干预：通过药理学手段抑制胆固醇合成，可以纠正耐药细胞中的脂质代谢异常，恢复CHAC1的表达和活性，进而重新激活铁死亡通路。这可能使耐药的肿瘤细胞重新对FGFR2b抑制剂敏感。例如，他汀类药物作为HMG-CoA还原酶抑制剂，能有效抑制胆固醇合成。研究探索将这类药物与FGFR2b靶向药物联用，以期逆转耐药，提高治疗效果。

PROTACs降解FGFR2的新策略

传统的FGFR抑制剂主要通过竞争性结合激酶ATP口袋来阻断FGFR2的活性，但这种抑制作用往往面临选择性差、耐药突变和剂量限制性毒性等问题 4950。蛋白质降解靶向嵌合体（PROTACs）技术作为一种新兴的药物开发策略，通过利用细胞内泛素-蛋白酶体系统（UPS）实现靶蛋白的降解，为克服FGFR抑制剂的耐药性提供了全新的途径。

  • PROTAC的工作原理：PROTAC分子通常包含三个部分：一个靶蛋白结合配体、一个E3泛素连接酶结合配体，以及连接两者的连接臂。PROTAC通过“桥接”靶蛋白和E3连接酶，促使靶蛋白被泛素化，进而被26S蛋白酶体降解。
  • FGFR2降解剂的优势：
    • 克服激酶域突变：PROTAC降解剂不依赖于激酶活性抑制，而是直接清除靶蛋白，因此有望克服FGFR2激酶域的二次突变（如V565F看门人突变）导致的耐药性 50。即使突变导致抑制剂结合亲和力下降，PROTAC仍能通过诱导降解来发挥作用 50。
    • 高选择性：研究表明，通过优化PROTAC结构，可以实现高度选择性的FGFR2降解，避免对FGFR1、FGFR3、FGFR4等其他FGFR亚型产生脱靶效应，从而降低与泛FGFR抑制相关的毒性（如高磷血症） 4950。
    • 持续性抑制：PROTACs以亚化学计量的方式发挥作用，即少量PROTAC分子即可催化大量靶蛋白的降解，实现持续性的靶蛋白清除，可能带来更持久的治疗效果。
  • 新型FGFR2降解剂N5和28e：
    • N5：研究基于泛FGFR抑制剂Erdafitinib与CRBN（一种E3连接酶配体）偶联，合成并鉴定了一种有效的FGFR2降解剂N5 49。N5对FGFR2表现出显著的特异性和极高的酶抑制活性（IC50 = 0.08 nM），在胃癌细胞中展现出强大的抗增殖活性（0.17 nM浓度下抑制率超过50%） 49。其作用机制包括诱导胃癌细胞周期停滞在G0/G1期，并通过降低FGFR下游蛋白水平来促进细胞凋亡 49。N5在体内也表现出良好的药代动力学特征（腹腔注射生物利用度74.8%），并在SNU16异种移植瘤模型中有效抑制肿瘤生长，且效力优于其母体抑制剂Erdafitinib 49。
    • 28e：另一项研究基于LY2874455开发了FGFR2选择性降解剂28e，对FGFR2的DC50达到0.645 nM，降解效率达86%，且基本不降解FGFR1、3、4亚型（DC50 > 300 nM） 50。28e能显著抑制FGFR2过表达细胞系（包括KATOIII、SNU16和AN3CA）的增殖，效力与母体抑制剂相当 50。更重要的是，28e在抑制FGFR2看门人突变异构体方面表现出优于母体抑制剂的激酶抑制活性（IC50 = 0.121 nM），显示出克服看门人突变耐药的潜力 50。

这些针对耐药机制的潜在策略为FGFR2b靶向治疗的未来发展描绘了广阔前景。通过多角度、多层次的干预，有望显著提高胃癌患者对FGFR2b靶向治疗的响应率和持久性。

4. FGFR2b作为生物标志物的检测与临床应用

FGFR2b在胃癌中的精准检测是实现靶向治疗的关键环节，其检测方法的标准化与验证对于筛选合适的患者至关重要。目前，常用的检测方法包括免疫组织化学（IHC）、荧光原位杂交（FISH）和循环肿瘤DNA（ctDNA）检测。

4.1 检测方法的标准化与验证

FGFR2b作为胃癌的一个新兴生物标志物，其检测方法的标准化和验证对于指导临床治疗、确保患者筛选的准确性具有决定性意义。不同的检测技术各有优劣，且结果的一致性受到多种因素的影响。

免疫组织化学 (IHC) 检测

IHC是目前最常用且相对经济便捷的蛋白表达水平检测方法，它通过特异性抗体与FGFR2b蛋白结合，并通过显色反应显示其在肿瘤细胞膜上的表达情况。

  • 检测标准：FGFR2b的IHC检测通常采用半定量评分系统，如基于膜染色的强度（0、1+、2+、3+）和阳性肿瘤细胞的百分比来评估。在FORTITUDE-101等大型临床试验中，FGFR2b阳性通常被定义为肿瘤细胞（TC）中度至强（2+/3+）的膜染色。例如，FORTITUDE-101试验中，FGFR2b过表达的定义是任意百分比的肿瘤细胞显示2+/3+膜染色，其中16.2%的患者达到≥10% TC 2+/3+阳性 11。
  • 优势：IHC能够直观地揭示FGFR2b蛋白在肿瘤组织中的异质性表达模式，例如，可以观察到同一肿瘤内FGFR2b染色强度和阳性细胞比例的不均一性 5152。此外，IHC操作相对简单，成本较低，易于在常规病理实验室推广。
  • 挑战与局限性：
    • 抗体特异性：需要高度特异性的抗体来区分FGFR2的不同亚型（FGFR2b和FGFR2c），并避免与其他FGFR家族成员的交叉反应 28。目前，针对FGFR2b特异性的抗体（如FPR2-D）已被开发并用于临床研究 51。
    • 判读标准统一性：由于判读存在一定主观性，不同病理医生之间的判读一致性可能存在差异，需要严格的培训和质量控制。
    • 样本质量影响：福尔马林固定石蜡包埋（FFPE）组织样本的固定时间、处理方式等都会影响抗原的完整性和可及性，进而影响染色结果的准确性 51。
    • 表达异质性：胃癌中FGFR2b的瘤内异质性较高，可能导致单点活检结果无法代表整个肿瘤的真实FGFR2b状态 52。
  • 标准化与优化：为提高IHC检测的准确性和可靠性，需要进行广泛的标准化和验证工作。例如，VENTANA FGFR2b (FPR2-D) 鼠单克隆抗体检测方法在不同实体瘤类型中进行了优化，针对胃/胃食管结合部腺癌有其特定的优化方案，以确保最佳染色性能 51。

荧光原位杂交 (FISH) 检测

FISH主要用于检测FGFR2基因的扩增或重排，这是一种常见的导致FGFR2b过表达的遗传学改变。

  • 检测标准：FISH通过荧光标记的探针与细胞核中的FGFR2基因序列结合，观察FGFR2基因拷贝数或FGFR2/CEN10（10号染色体着丝粒探针）比值来判断是否存在基因扩增。
  • 优势：FISH作为一种细胞遗传学技术，具有较高的敏感度和特异性，能够直接检测基因拷贝数异常。
  • 挑战与局限性：
    • 操作复杂：FISH操作相对复杂，对技术人员要求较高，且成本较IHC高。
    • 不完全相关性：虽然基因扩增常导致蛋白过表达，但并非所有FGFR2b过表达都由基因扩增引起，反之亦然。一些FGFR2b高表达的肿瘤可能没有FISH检测到的基因扩增，这提示存在其他调节机制。
    • 瘤内异质性：肿瘤中FGFR2基因扩增的异质性可能导致活检结果不完全反映肿瘤的整体状态。
  • 中心实验室验证对患者筛选的重要性：鉴于上述各种检测方法的特点和局限性，特别是在胃癌FGFR2b表达的高度异质性背景下，中心实验室验证对于FGFR2b靶向治疗的患者筛选显得尤为重要。

循环肿瘤DNA (ctDNA) 检测

ctDNA检测是一种非侵入性检测方法，通过分析血液中肿瘤细胞释放的DNA碎片来获取肿瘤的遗传信息，包括FGFR2基因的拷贝数变异。

  • 检测标准：ctDNA检测通常利用二代测序（NGS）技术，通过评估FGFR2的扩增状态。

  • 优势：

    • 非侵入性：ctDNA检测无需组织活检，可重复取样。
    • 动态监测：便于动态监测肿瘤的分子状态，尤其适用于组织活检困难或存在多发转移病灶的患者。

  • 挑战与局a限性：

    • 敏感性：ctDNA的含量可能较低，尤其是在早期肿瘤或肿瘤负荷较小的患者中，检测敏感性可能不足。
    • 技术复杂性与成本：NGS技术相对复杂且成本较高，需要专业的分析平台和生物信息学支持。
    • 临床验证：在胃癌FGFR2b检测中的临床有效性和预测价值仍需更多大规模临床研究的验证。

  • 确保结果一致性：通过统一的检测平台、标准化的操作流程、严格的质量控制以及经验丰富的病理学家进行集中判读，可以最大程度地减少技术误差和主观偏差，确保检测结果的准确性和可重复性。

  • 指导临床试验：在FORTITUDE-101等关键临床试验中，采用中心实验室进行FGFR2b IHC检测，并设定了明确的阳性标准（如≥10% TC 2+/3+）来筛选患者，这是确保试验结果可靠性和指导未来临床实践的基础 11。这种做法有助于将生物标志物检测与药物疗效紧密关联，从而筛选出最有可能从靶向治疗中获益的患者群体 53。

  • 未来展望：未来FGFR2b检测需要整合多种技术，例如在IHC或FISH初筛后，通过ctDNA进行动态监测和异质性评估，以提供更全面、准确的生物标志物信息，从而实现真正的个体化精准治疗。

4.2 与其他生物标志物的共表达与分层价值

在胃癌复杂而异质的分子图谱中，FGFR2b作为单一生物标志物，其临床应用价值不仅体现在独立预测治疗反应上，更在于其与其他关键生物标志物（如HER2、CLDN18.2、PD-L1）的共表达模式及由此带来的分层价值。理解这些共表达关系有助于更精准地进行患者分型，并指导联合治疗策略的制定。

FGFR2b与其他可操作标志物的重叠度

一项针对胃癌和胃食管结合部癌（GC/GEJC）患者的回顾性队列研究详细分析了FGFR2b与HER2、PD-L1和CLDN18.2等标志物的共表达情况12：

  • FGFR2b与HER2、PD-L1、CLDN18.2的重叠有限：在FGFR2b阳性（任意>0%肿瘤细胞显示中度2+或强3+膜染色）的肿瘤样本中，53.9%（95% CI 42.1%至65.5%）的肿瘤对其他已评估的可操作生物标志物（包括HER2、PD-L1的CPS≥5或CLDN18.2）呈阴性 12。这意味着FGFR2b阳性患者中有超过一半的比例缺乏其他可操作的靶向或免疫治疗标志物，提示FGFR2b靶向治疗能够识别一个独特的胃癌患者亚群12。
  • 具体重叠率：
    • 在FGFR2b阳性肿瘤中，HER2阳性的比例为2.6% 12。
    • PD-L1 CPS≥5阳性的比例为15.6% 12。
    • 这些数据表明，FGFR2b阳性肿瘤与其他主流可操作标志物的共表达率较低，进一步强调了FGFR2b作为一个独立生物标志物的潜力，能够定义一个独特的、可能从FGFR2b靶向疗法中获益的患者群体12。

多维度生物标志物组合在精准分型中的应用

胃癌的高度异质性决定了单一生物标志物可能不足以指导最佳治疗方案。整合FGFR2b与其他标志物信息，进行多维度分型，有助于更精细地划分患者亚群，为个体化治疗提供依据。

  1. FGFR2b与其他致癌通路的互补性：

    • FGFR2b和HER2：虽然二者共表达率低，但在少数同时阳性的患者中，可能需要联合靶向治疗或序贯治疗，以克服单一靶向的局限性。FGFR2b靶向治疗被认为是HER2阴性胃癌患者的潜在治疗选择54。
    • FGFR2b和PD-L1：对于同时伴有PD-L1高表达的FGFR2b阳性患者，未来可能需要进一步探索FGFR2b抑制剂与免疫检查点抑制剂的联合策略。
    • FGFR2b和CLDN18.2：CLDN18.2也是胃癌中一个重要的新兴生物标志物，zolbetuximab等药物已在此领域取得进展55。FGFR2b与CLDN18.2均为胃癌的潜在靶点53。
    • FGFR2b与其他FGFR基因变异：FGFR2b过表达虽然与FGFR2基因扩增高度相关，但并非所有FGFR2b高表达都由扩增引起，提示可能存在其他如基因重排或mRNA高表达等机制26。综合IHC、FISH和NGS（检测基因扩增、突变和融合）等多种检测手段，可以更全面地评估FGFR2状态，从而精准指导FGFR抑制剂的选择。

  2. 分子分型指导下的治疗决策：

    • FGFR2b阳性、其他标志物阴性的患者，可优先考虑FGFR2b靶向治疗（如bemarituzumab联合化疗）12。
    • 对于同时伴有其他可操作标志物（如PD-L1高表达）的FGFR2b阳性患者，可探索联合治疗策略，例如FGFR2b抑制剂与免疫检查点抑制剂的组合。

  3. 克服肿瘤异质性：胃癌存在显著的空间异质性（原发灶与转移灶之间、肿瘤不同区域之间）和时间异质性（治疗前后），这可能导致生物标志物表达的动态变化2056。因此，多维度生物标志物组合检测，尤其是结合液体活检（ctDNA）进行动态监测，将有助于克服单次活检的局限性，更好地反映肿瘤的整体分子状态和演变，从而及时调整治疗方案。

综上所述，FGFR2b与其他生物标志物的共表达分析具有重要的临床意义。通过构建多维度生物标志物组合，可以更精确地识别胃癌患者亚群，优化治疗选择，从而推动胃癌精准医疗的发展。

4.3 动态监测与治疗决策调整

胃癌的治疗是一个动态过程，肿瘤的分子特性并非一成不变。FGFR2b作为重要的生物标志物，其表达状态在治疗过程中可能发生改变，尤其是在原发灶与转移灶之间以及治疗前后。因此，对FGFR2b表达进行动态监测，并利用液体活检等技术实现实时监测，对于耐药预警和治疗方案的及时调整具有重要的指导意义。

治疗过程中FGFR2b表达的动态变化

肿瘤内部存在异质性，这意味着FGFR2b的表达水平可能在不同的肿瘤区域或不同的时间点上发生变化，这对于靶向治疗的有效性构成挑战。

  • 原发灶与转移灶表达的异质性：研究表明，FGFR2b的表达在原发肿瘤和其匹配的转移灶之间存在显著的不一致性。例如，一项针对胃癌原发灶和腹膜转移灶的研究发现，FGFR2b的表达具有高度的空间异质性，仅有少数病例在原发灶和腹膜转移灶中均呈阳性 20。更进一步的分析显示，腹膜转移灶中FGFR2b的表达水平甚至可能低于原发灶 57。这意味着如果仅基于原发灶的活检结果来指导针对转移灶的治疗，可能会出现假阴性，导致患者错失潜在的FGFR2b靶向治疗机会。因此，在评估转移性疾病患者时，特别是对于腹膜转移，最好同时检测原发灶和转移灶的FGFR2b状态 20。
  • 治疗前后的动态变化：肿瘤在治疗压力下会发生适应性改变，这可能导致FGFR2b表达的下调或上调。例如，对FGFR2b靶向治疗产生耐药性的肿瘤细胞可能会降低FGFR2b的表达以逃避药物作用，或者激活旁路通路。这种动态变化提示，在疾病进展时，需要重新评估FGFR2b状态，以指导后续治疗选择。

基于液体活检的实时监测在耐药预警、方案切换中的指导意义

液体活检，特别是通过检测循环肿瘤DNA（ctDNA）来评估FGFR2基因的拷贝数变异或突变，为实时、非侵入性地动态监测FGFR2b状态提供了可能。

  • 克服组织活检局限性：传统组织活检是侵入性的，难以多次重复取样，且可能因肿瘤异质性而无法全面反映肿瘤的真实分子状态。液体活检则能够克服这些局限性，可以更频繁地进行，提供实时的肿瘤分子信息，反映肿瘤整体的分子特征 58。
  • 耐药预警：在FGFR2b靶向治疗期间，通过定期检测ctDNA中FGFR2基因拷贝数的变化或耐药相关突变的出现（如FGFR2的二次突变），可以实现耐药的早期预警。例如，ctDNA中FGFR2拷贝数的再次升高可能预示着治疗耐药的发生或肿瘤负荷的增加。此外，如果发现与FGFR2抑制剂耐药相关的融合基因（如WDR11-AS1-FGFR2融合基因）或高水平的FGFR2扩增，可能提示肿瘤的侵袭性疾病进程和对标准治疗的抵抗 58。早期发现这些分子事件，可以为临床医生提供窗口期，及时调整治疗方案，避免疾病进展。
  • 指导方案切换：
    • 从FGFR2b靶向治疗切换到其他方案：当ctDNA监测显示FGFR2b靶向治疗出现耐药机制（例如，出现FGFR2二次突变或旁路激活的证据），或FGFR2b表达显著降低时，可以考虑停止FGFR2b靶向药物，切换至其他治疗策略，如化疗、免疫治疗或其他靶向药物。
    • 从其他方案切换到FGFR2b靶向治疗：对于初始未检测到FGFR2b过表达的患者，如果疾病进展后通过液体活检发现FGFR2基因扩增或FGFR2b高表达，可能提示FGFR2b克隆在治疗压力下被筛选出来或扩增，此时重新启用FGFR2b靶向治疗可能获益。
    • 甲基化状态的监测：除了基因扩增和突变，FGFR2基因启动子区域的甲基化状态也可能影响其表达。例如，FGFR2启动子的低甲基化与胃癌的发生发展相关，并可作为早期诊断的潜在生物标志物 59。虽然目前主要用于诊断，但未来不排除通过动态监测甲基化状态来评估FGFR2b的表达潜力，从而指导治疗方案的选择。
  • 筛选新一代药物：如果ctDNA检测到FGFR2的耐药突变（如看门人突变V565F），则可考虑使用能克服这些突变的新一代FGFR抑制剂或PROTAC降解剂。

总之，FGFR2b表达的动态变化和异质性是胃癌治疗中不可忽视的因素。通过结合组织活检和液体活检，实现对FGFR2b状态的实时、多维度监测，将有助于临床医生更准确地评估患者对治疗的响应，及时预警耐药，并合理调整治疗策略，从而最大程度地优化患者的治疗效果和生存预后。

5. 胃癌FGFR2b靶向治疗的竞争格局与未来趋势

5.1 现有管线的研发阶段与企业布局

胃癌FGFR2b靶向治疗领域正经历快速发展，多个候选药物在全球范围内进行临床研究，其中单克隆抗体bemarituzumab凭借其在II期临床试验中的积极数据，已成为该领域最受关注的药物之一。FGFR2b靶向药物的研发主要集中在晚期胃癌及胃食管结合部腺癌（GC/GEJC），并逐步向辅助治疗等更早期的适应症探索。

Bemarituzumab (FPA144) 的研发进展与企业布局

  • 研发阶段：Bemarituzumab（由Five Prime Therapeutics研发，后被Amgen收购，并与Zai Lab合作开发）是目前进展最快、最受瞩目的FGFR2b特异性单克隆抗体。该药物已完成II期FIGHT研究，结果显示在FGFR2b过表达（≥10%肿瘤细胞2+/3+）的晚期GC/GEJC患者中，联合mFOLFOX6化疗方案可改善无进展生存期（PFS），尽管尚未达到统计学显著性（HR 0.68, p=0.073）32。目前，bemarituzumab正处于III期临床试验阶段，包括FORTITUDE-101 (NCT05052801) 和FORTITUDE-102 (NCT05111626) 研究。FORTITUDE-101旨在评估bemarituzumab联合mFOLFOX6作为一线治疗在FGFR2b阳性晚期或转移性GC/GEJC患者中的疗效和安全性。FORTITUDE-102则探索其在辅助治疗中的潜力。
  • 适应症覆盖：主要聚焦于HER2阴性、FGFR2b过表达的晚期或转移性GC/GEJC患者的一线治疗，并探索辅助治疗等潜在适应症。
  • 企业竞争态势：最初由Five Prime Therapeutics开发，2021年被Amgen以19亿美元收购，彰显了Amgen对该靶点的看好。Amgen进一步将bemarituzumab在大中华区的开发和商业化权益授权给再鼎医药（Zai Lab），扩大了其全球市场布局。这种合作模式旨在加速药物在不同地域的审批和市场推广，共同分享潜在的巨大市场份额。Bemarituzumab作为“首创”（first-in-class）的FGFR2b单克隆抗体，目前在胃癌领域尚无直接竞争的同类上市药物，因此占据了领先地位30。

JNJ-61186372 (Janssen) 的研发进展

  • 研发阶段：JNJ-61186372是强生（Johnson & Johnson）旗下杨森制药（Janssen）正在开发的一款FGFR2b靶向抗体。该药物目前处于I期临床试验阶段 (NCT05353140)，旨在评估其在FGFR2b阳性实体瘤患者中的安全性、药代动力学和初步疗效。
  • 适应症覆盖：JNJ-61186372的临床开发涵盖了FGFR2b过表达的多种实体瘤，包括胃癌，目前主要作为探索性疗法，其在胃癌领域的具体临床数据尚未公布。
  • 企业竞争态势：作为后来者，Janssen的JNJ-61186372面临bemarituzumab的先发优势，其未来市场表现将取决于其临床数据，特别是在与bemarituzumab相比较时的差异化优势（例如更高的应答率、更低的毒性或更长的缓解持续时间），以及其可能拓展的适应症范围。

其他FGFR抑制剂的布局

除了上述针对FGFR2b的特异性抗体，广谱或选择性FGFR小分子酪氨酸激酶抑制剂（FGFR-TKI）也在其他瘤种中取得进展，但在胃癌FGFR2b过表达领域，其疗效和安全性尚未达到突破性水平。

  • 泛FGFR-TKI：如erdafitinib和pemigatinib已获FDA批准用于治疗FGFR2/3突变的尿路上皮癌和FGFR2融合的胆管癌60。但在胃癌中，小分子抑制剂的单药客观缓解率（ORR）偏低，且存在高磷血症等剂量限制性毒性，限制了其在FGFR2b过表达胃癌中的应用潜力。
  • 新型FGFR-TKI和PROTACs：针对FGFR2耐药突变而开发的新型小分子抑制剂和PROTACs（靶向蛋白质降解剂）正处于早期研发阶段。这些药物可能在未来改变竞争格局，特别是如果它们能有效克服现有药物的耐药性或提供更优的安全性60。

总体竞争格局

目前，FGFR2b靶向治疗的竞争格局主要由bemarituzumab主导，尤其是在晚期GC/GEJC的一线治疗领域。随着III期临床试验数据的成熟，bemarituzumab有望成为首个上市的FGFR2b靶向药物，从而确立其在胃癌治疗中的市场地位。其他在研药物，包括Janssen的JNJ-61186372以及下一代小分子抑制剂和PROTACs，则需要通过展示更优的临床益处或克服现有药物的局限性来寻求差异化竞争优势。未来的竞争将围绕疗效、安全性、耐药管理和患者选择策略展开。

5.2 差异化竞争的关键方向

在胃癌FGFR2b靶向治疗领域，随着现有管线的不断发展和新技术的涌现，差异化竞争成为市场占位的关键。新型药物通过作用机制的创新、适应症的拓展以及患者富集的优化，力求在激烈的市场中脱颖而出。

新型药物与传统药物的优势对比

  1. Afucosylated抗体增强ADCC：以Bemarituzumab为例

    • 优势：Bemarituzumab是一种去岩藻糖基化（afucosylated）的单克隆抗体，其最显著的特点是Fc区的岩藻糖（fucose）被去除。这种修饰显著增强了抗体对人Fcγ受体IIIa的亲和力，从而极大地提高了抗体依赖性细胞介导的细胞毒性（ADCC）效应 30。ADCC是免疫系统清除肿瘤细胞的重要机制，通过召集自然杀伤（NK）细胞等免疫细胞直接杀伤被抗体标记的肿瘤细胞。相比于未进行afucosylation修饰的传统抗体，bemarituzumab能够更有效地激活免疫反应，实现更强的肿瘤细胞杀伤力 30。此外，bemarituzumab还具有直接抑制FGFR2b信号转导的能力，形成双重作用机制 30。
    • 传统药物对比：传统的非afucosylated抗体或小分子抑制剂通常缺乏这种增强的免疫效应。小分子FGFR-TKI主要通过抑制FGFR激酶活性来发挥作用，但缺乏免疫调节功能。因此，afucosylated抗体在免疫激活方面具有独特优势，有望为患者带来更深层次、更持久的缓解。

  2. 共价抑制剂克服耐药：以Futibatinib为例

    • 优势：Futibatinib（TAS-120）是一种不可逆的共价FGFR抑制剂，其通过与FGFR激酶结构域中的特定半胱氨酸残基形成共价键，实现对靶点的持久抑制。这种共价结合机制使其能够更有效地克服FGFR2的一些点突变，从而可能延缓或克服由FGFR2变异引起的获得性耐药。此外，共价抑制剂通常具有更高的靶点结合率和更长的靶点抑制时间，即使药物在体内浓度波动，也能维持持续的药效。
    • 传统药物对比：传统的非共价小分子FGFR-TKI，如AZD4547，主要通过可逆性结合，其抑制效果受药物浓度和靶点亲和力的影响较大，容易在药物浓度下降时出现靶点再激活，或因靶点突变导致结合亲和力降低而产生耐药。共价抑制剂在理论上能提供更强大和持久的抑制，并可能应对更广泛的耐药突变，这是其显著的差异化优势。

  3. PROTACs降解FGFR2的新策略

    • 优势：靶向蛋白质降解嵌合体（PROTACs）代表了一种全新的药物开发范式，它通过诱导泛素-蛋白酶体系统介导的靶蛋白降解，而非简单抑制其功能。这种机制的优势在于：
      • 克服激酶域突变：PROTAC不依赖于激酶活性抑制，而是直接清除靶蛋白，因此有望克服FGFR2激酶域的二次突变（如“看门人”突变V565F）导致的耐药性。
      • 高选择性与低剂量：PROTAC通过催化循环发挥作用，即少量PROTAC分子即可降解大量靶蛋白，有望实现低剂量给药和更小的脱靶毒性。
      • 持续性抑制：靶蛋白的降解而非暂时抑制，意味着即使PROTAC药物浓度较低，也能维持较长时间的FGFR2清除，从而实现更持久的药效。
    • 传统药物对比：PROTAC在作用机制上与传统小分子抑制剂和抗体完全不同，其独特之处在于“降解”而非“抑制”，这使其在克服耐药性和实现持久疗效方面具有潜在的颠覆性优势。目前，FGFR2 PROTACs仍处于早期研究阶段，但其前景广阔。

适应症扩展与患者富集对市场占位的影响

  1. 适应症扩展：从晚期治疗到围手术期治疗

    • 围手术期治疗的潜力：目前FGFR2b靶向药物主要集中在晚期或转移性胃癌的一线治疗。然而，将这些药物应用于围手术期（新辅助/辅助）治疗具有巨大的潜力。在胃癌根治性手术前进行新辅助治疗，可以缩小肿瘤、降低分期、提高手术切除率（R0切除），并可能消除微小转移灶。术后辅助治疗则旨在清除残余肿瘤细胞，降低复发风险。
    • 市场占位影响：如果FGFR2b靶向药物能在围手术期治疗中显示出显著的临床益处，例如提高R0切除率、延长无复发生存期（DFS）或总生存期（OS），将极大拓展其市场空间，并确立其在胃癌全程管理中的关键地位。目前，Bemarituzumab的FORTITUDE-102研究正在探索其作为辅助治疗的潜力，预示着该领域的新发展。

  2. 患者富集：高表达亚组的临床价值

    • 精准筛选的重要性：在FGFR2b靶向治疗中，患者的精准富集对提升疗效至关重要。通过更严格的生物标志物筛选标准来富集患者，可以显著提高治疗的有效性。
    • 市场占位影响：专注于FGFR2b高表达患者亚组，不仅能够提高临床试验的成功率和药物的临床疗效，还能为药物获得更明确的监管批准和市场定位提供有力证据。这种“少即是多”的策略，即针对更精准的患者群体提供更显著的临床获益，将有助于药物在特定细分市场中占据主导地位，并形成差异化优势。此外，这也推动了对FGFR2b检测方法的标准化和验证，以确保能够准确识别这些高表达患者 1128。

通过这些差异化的竞争方向，新型FGFR2b靶向药物有望克服现有挑战，为胃癌患者提供更有效、更精准的治疗方案，并在未来的市场格局中占据一席之地。

5.3 未来发展的挑战与机遇

胃癌FGFR2b靶向治疗的未来发展充满潜力，但同时也面临诸多挑战，尤其是在异质性检测、耐药管理和联合方案优化方面。然而，随着空间组学、类器官药敏测试等新技术的不断涌现，以及多靶点联合治疗策略的深入探索，FGFR2b靶向治疗有望迎来新的突破，为胃癌患者带来更精准、高效的个体化治疗方案。

挑战

  1. 异质性检测的复杂性：
    • 肿瘤内/间异质性：FGFR2b在胃癌中的表达存在显著的肿瘤内异质性（同一肿瘤不同区域表达不均一）和肿瘤间异质性（原发灶与转移灶之间表达不一致）56。这使得传统单点活检难以全面准确地反映肿瘤的FGFR2b状态，可能导致患者筛选的假阴性，使部分潜在受益患者错失治疗机会。
    • 检测方法标准化：尽管IHC是常用的检测手段，但其判读的主观性和标准化不足，以及与FISH（基因扩增）和ctDNA（拷贝数）结果的不完全一致性，都给精准筛选患者带来了挑战。需要更可靠、可重复的生物标志物检测方法和统一的判读标准61。
  2. 耐药管理的艰巨性：
    • 原发性耐药：部分患者在治疗开始时即对FGFR2b抑制剂不敏感，其分子基础涉及肿瘤微环境和肿瘤细胞内在机制。
    • 获得性耐药：长期治疗后，肿瘤细胞通过FGFR2二次突变（如“看门人”突变）、旁路信号通路激活（如IGF-1R、FGFR1、MET、HER3、EGFR等）或基因融合等机制产生耐药，导致疾病进展。如何有效识别和克服这些复杂的耐药机制是亟待解决的问题。
  3. 联合方案优化的复杂性：
    • 药物选择与配比：FGFR2b抑制剂与化疗、免疫治疗或其他靶向药物的联合方案虽然显示出协同增效潜力，但最佳的药物选择、剂量配比和给药顺序仍需大量临床研究探索。
    • 毒性管理：联合治疗可能增加不良反应的发生率和严重程度，如何在提高疗效的同时控制毒性，是临床实践中需要平衡的关键问题。

机遇与未来前景

  1. 空间组学在个体化治疗中的应用前景：

    • 解析肿瘤微环境：空间组学技术能够以前所未有的分辨率，在保留组织空间信息的同时，分析肿瘤及其微环境中细胞的基因表达、蛋白丰度等分子特征62。这有助于深入理解FGFR2b在肿瘤微环境中的确切作用，揭示FGFR2b信号通路与其他信号通路（如免疫检查点、代谢通路）之间的相互作用。
    • 克服异质性检测挑战：通过对肿瘤切片进行空间转录组学或空间蛋白质组学分析，可以更全面地评估FGFR2b及其相关通路的表达模式和细胞分布，从而更精准地识别FGFR2b高表达区域，克服传统活检样本量有限和异质性造成的检测盲区。这也有助于理解原发性耐药的TME分子基础。
    • 发现新型生物标志物：空间组学可能揭示与FGFR2b表达相关的新的预后或预测生物标志物，指导更精细的患者分层和治疗选择。

  2. 类器官药敏测试指导精准用药：

    • 体外药效预测：肿瘤类器官（Organoids）是体外三维培养的、高度模拟原发肿瘤组织结构和分子特征的模型。利用患者来源的肿瘤类器官进行药物敏感性测试（PDOX模型），可以模拟不同FGFR2b靶向药物及其联合方案的体外药效，从而为个体化治疗方案的选择提供重要参考63。
    • 耐药机制研究：类器官模型还可以用于深入研究FGFR2b靶向治疗的耐药机制，例如在体外诱导耐药类器官，并对其进行基因组学、转录组学分析，以发现新的耐药驱动基因或通路。
    • 指导联合用药：通过在类器官模型中测试不同药物组合的协同效应，可以筛选出最佳的联合治疗方案，减少临床试验的盲目性。

  3. FGFR2b与CLDN18.2等多靶点联合治疗的协同潜力：

    • CLDN18.2作为另一重要靶点：CLDN18.2（Claudin 18.2）是胃癌中另一个新兴的、具有巨大潜力的治疗靶点，其靶向抗体zolbetuximab已在临床试验中显示出显著疗效，并有望获批上市556164。CLDN18.2在部分胃癌患者中表达61。
    • 协同作用的理论基础：FGFR2b和CLDN18.2在胃癌中的表达可能存在一定的重叠。理论上，对于同时表达FGFR2b和CLDN18.2的患者，联合靶向治疗可能通过双重阻断致癌通路，实现更强大的抗肿瘤协同效应。
    • 研究方向：未来的研究可以探索FGFR2b靶向药物（如bemarituzumab）与CLDN18.2靶向药物（如zolbetuximab）的联合治疗方案，以期在更广泛的患者群体中获得更优的临床效果。这种多靶点协同策略有望克服单一靶点治疗的局限性，特别是在胃癌高度异质性的背景下。

综上所述，虽然FGFR2b靶向治疗在胃癌领域仍面临挑战，但随着分子生物学、组学和药物开发技术的不断进步，这些挑战有望被逐步克服。空间组学、类器官模型以及多靶点联合治疗策略的探索，将共同推动FGFR2b靶向治疗走向更加精准和个体化的未来，最终改善胃癌患者的预后和生活质量。

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参考文献

1The receptor tyrosine kinase FGFR2b/KGFR controls early differentiation of human keratinocytes.PubMed

Francesca Belleudi, Valeria Purpura, Maria Rosaria Torrisi
PLoS One. 2011;6(9):e24194. doi: 10.1371/journal.pone.0024194. Epub 2011 Sep 21.
The FGFRs trigger divergent responses, such as proliferation and differentiation, and the cell type as well as the context-dependent signaling are crucial for the functional outcome. The FGFR2b/KGFR is expressed exclusively on epithelial cells and plays a key role in skin homeostasis. Here we analyzed in vitro the role of KGFR in the early differentiation of keratinocytes modulating its expression by KGFR cDNA transient transfection or KGFR siRNA microinjection and inducing a synchronous wave of differentiation in pre-confluent cells. Immunofluorescence, biochemical and molecular approaches demonstrated that KGFR overexpression increased the early differentiation marker keratin 1 at both transcriptional and translational levels, while receptor depletion reduced it. Ligand-dependent receptor activation and signaling were required for this differentiative effect. Overexpression of kinase negative KGFR mutant or Tyr769 KGFR signaling mutant, which is not able to recruit and activate PLC-γ, showed that the receptor kinase activity, but not its PLCγ-mediated signaling, is required for differentiation. Reduction of K1 expression, obtained by AKT inhibition, demonstrated that the PI3K/Akt signaling pathway is involved in the control of KGFR-mediated keratinocyte differentiation. This in vitro experimental model indicates that FGFR2b/KGFR expression represents a key event regulating keratinocyte early differentiation during the switch from undifferentiated to differentiating cells.

2Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome.PubMed

O A Ibrahimi, A V Eliseenkova, A N Plotnikov, et al.
Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7182-7. doi: 10.1073/pnas.121183798. Epub 2001 Jun 5.
Apert syndrome (AS) is characterized by craniosynostosis (premature fusion of cranial sutures) and severe syndactyly of the hands and feet. Two activating mutations, Ser-252 --> Trp and Pro-253 --> Arg, in fibroblast growth factor receptor 2 (FGFR2) account for nearly all known cases of AS. To elucidate the mechanism by which these substitutions cause AS, we determined the crystal structures of these two FGFR2 mutants in complex with fibroblast growth factor 2 (FGF2). These structures demonstrate that both mutations introduce additional interactions between FGFR2 and FGF2, thereby augmenting FGFR2-FGF2 affinity. Moreover, based on these structures and sequence alignment of the FGF family, we propose that the Pro-253 --> Arg mutation will indiscriminately increase the affinity of FGFR2 toward any FGF. In contrast, the Ser-252 --> Trp mutation will selectively enhance the affinity of FGFR2 toward a limited subset of FGFs. These predictions are consistent with previous biochemical data describing the effects of AS mutations on FGF binding. Alterations in FGFR2 ligand affinity and specificity may allow inappropriate autocrine or paracrine activation of FGFR2. Furthermore, the distinct gain-of-function interactions observed in each crystal structure provide a model to explain the phenotypic variability among AS patients.

3Expression and function of fibroblast growth factor (FGF) 7 during liver regeneration.PubMed

Su-Mei Tsai, Wen-Pin Wang
Cell Physiol Biochem. 2011;27(6):641-52. doi: 10.1159/000330073. Epub 2011 Jun 17.
BACKGROUND/AIM: Previous studies have shown that fibroblast growth factors (FGFs) are involved in the process of liver injury repair. Liver regeneration after partial hepatectomy (PH) is impaired in transgenic mice expressing dominant-negative FGFR2b in hepatocytes. Although FGF7, a ligand specifically bound to FGFR2b, is expressed by activated hepatic stellate cells (HSCs) in fibrotic livers, the expressions and functions of FGF7 and FGFR2b after PH remain unexplored. Therefore, this study sought to examine the potential role of FGF7 signaling during liver regeneration. METHODS: We examined the expression of FGF7 and FGFR2b in normal and regenerating livers. Effects of FGF7 on hepatocytes were examined in vitro using primary hepatocyte culture with FGF7 recombinant protein and in vivo by hydrodynamic-based gene transfer method. RESULTS: We found that FGF7 expression was increased according to the activation status of HSCs after PH. The receptor, FGFR2b, was also increased in hepatocytes during liver regeneration. In vitro treatment with FGF7 protein activated ERK1/2 and promoted proliferation of hepatocytes isolated from regenerating livers. In vivo overexpression of exogenous FGF7 could notably promote hepatic proliferation and activate MAPKs after PH. CONCLUSION: This study suggests a role for activated HSC-expressed FGF7 in stimulating FGF signaling pathways in hepatocytes and regulating liver regeneration.

4Elf5 is an epithelium-specific, fibroblast growth factor-sensitive transcription factor in the embryonic lung.PubMed

David E Metzger, Yan Xu, John M Shannon
Dev Dyn. 2007 May;236(5):1175-92. doi: 10.1002/dvdy.21133.
Fibroblast growth factor (FGF) signaling has been shown to be essential for many aspects of normal lung development. To determine epithelial targets of FGF signaling, we cultured embryonic day (E) 11.5 mouse lungs for 24 hr in the presence or absence of the FGF receptor antagonist SU5402, which inhibited branching morphogenesis. Affymetrix gene chip analysis of treated and control epithelia identified several genes regulated by FGF signaling, including Elf5, a member of the Epithelial-specific Ets family of transcription factors. SU5402 reduced Elf5 expression in mesenchyme-free cultures of E12.5 epithelium, demonstrating that the inhibition was direct. In situ hybridization revealed that Elf5 had a dynamic pattern of expression during lung development. We found that expression of Elf5 was induced by FGF7 and FGF10, ligands that primarily bind FGFR2b. To further define the pathways by which FGFs activate Elf5 expression, we cultured E11.5 lung tips in the presence of compounds to inhibit FGF receptors (SU5402), PI3-Kinase/Akt-mediated signaling (LY294002), and MAP Kinase/Erk-mediated signaling (U0126). We found that SU5402 and LY294002 significantly reduced Elf5 expression, whereas U0126 had no effect. LY294002 also reduced Elf5 expression in cultures of purified epithelium. Finally, pAkt was coexpressed with Elf5 in the proximal epithelial airways of E17.5 lungs. These results demonstrate that Elf5 is an FGF-sensitive transcription factor in the lung with a dynamic pattern of expression and that FGF regulation of Elf5 by means of FGFR2b occurs through the PI3-Kinase/Akt pathway.

5Up-regulation and co-expression of fibroblast growth factor receptors in human gastric cancer.PubMed

E Y Shin, B H Lee, J H Yang, et al.
J Cancer Res Clin Oncol. 2000 Sep;126(9):519-28. doi: 10.1007/s004320000128.
Fibroblast growth factor (FGF), a key regulatory factor of cell growth and differentiation, is involved in embryonic development, angiogenesis, and tumorigenesis. To date, four different FGF receptors (FGFRs) have been cloned and characterized. We examined the expression of four FGFRs in human gastric cancer tissues and cell lines using Northern analysis, ribonuclease protection assay, and immunohistochemistry. The mRNAs of FGFR-1 (10/14), FGFR-2 (9/14), and FGFR-4 (9/14) were up-regulated in cancer compared with normal tissues. FGFR-3 mRNAs were barely detectable in both normal and cancer tissues. These FGFR mRNAs were co-expressed in various combinations of two or three in the same tissue. Immunohistochemistry confirmed specific staining of multiple FGFRs, except FGFR-3, in the cancer specimens. To investigate the functional significance of FGFR co-expression we examined the invasive property of SNU-16 cells, which exhibited gene amplification of FGFR-2, -3, and -4 as well as over-expression of keratinocyte growth factor receptor (KGFR), a splice variant of FGFR-2, and FGFR-4 mRNA. KGF plus acidic FGF (aFGF), KGF, and aFGF treatment enhanced the invasive potential of SNU-16 cells over the control by 100%, 107%, and 47%, respectively, indicating that neither additive nor synergistic effect was induced by stimulation with aFGF plus KGF. These results suggest that co-expression of FGFRs in various combinations may cause subtle changes in the progression of gastric cancer.

6FGF7/FGFR2 signal promotes invasion and migration in human gastric cancer through upregulation of thrombospondin-1.PubMed

Tingting Huang, Lei Wang, Dian Liu, et al.
Int J Oncol. 2017 May;50(5):1501-1512. doi: 10.3892/ijo.2017.3927. Epub 2017 Mar 22.
Fibroblast growth factor 7 (FGF7) is a mesenchyme-specific heparin-binding growth factor that binds FGF receptor 2 (FGFR2) to regulate numerous cellular and physiological processes. FGF7/FGFR2 signal is associated with gastric cancer progression. In the present study, we investigated the molecular mechanism by which FGF7/FGFR2 promotes invasion and migration in human gastric cancer. We first demonstrated that increased FGFR2 expression in human gastric cancer tissues was significantly associated with tumor depth and clinical stage in human gastric cancer tissues. Thrombospondin 1 (THBS1) is an extracellular glycoprotein that plays multiple roles in cell-matrix and cell-cell interactions. Increased expression of THBS1 significantly correlated with tumor differentiation. FGFR2 and THBS1 expression were both increased in cancer tissues as compared with adjacent normal tissues and their expression was positively correlated. In vitro, FGF7 stimulation of cell invasion and migration was partially suppressed by the FGFR2 knockdown. In addition, FGF7/FGFR2 upregulated THBS1, and cell invasion and migration were decreased by knockdown of THBS1. Furthermore, the PI3K/Akt/mTOR signaling pathway was predominantly responsible for FGF7/FGFR2-induced THBS1 upregulation. Taken together, our data suggest that FGF7/FGFR2/THBS1 is associated with the regulation of invasion and migration in human gastric cancer.

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Monica Nanni, Danilo Ranieri, Benedetta Rosato, et al.
Mol Cell Biol. 2018 Jun 14;38(13). doi: 10.1128/MCB.00119-18. Print 2018 Jul 1.
Fibroblast growth factor receptor 2b (FGFR2b) is a receptor tyrosine kinase expressed exclusively in epithelial cells. We previously demonstrated that FGFR2b induces autophagy and that this process is required for the triggering of FGFR2b-mediated early differentiation of keratinocytes. However, the molecular mechanisms regulating this interplay remain to be elucidated. Since we have also recently shown that Jun N-terminal protein kinase 1 (JNK1) signaling is involved in FGFR2b-induced autophagy and a possible role of the JNK pathway in epidermal differentiation has been suggested (though it is still debated), we investigated here the cross talk between FGFR2b-mediated autophagy and differentiation, focusing on the downstream JNK signaling. Biochemical, molecular, and immunofluorescence approaches in 2-dimensional (2-D) keratinocyte cultures and three-dimensional (3-D) organotypic skin equivalents confirmed that FGFR2b overexpression increased both autophagy and early differentiation. The use of FGFR2b substrate inhibitors and the silencing of JNK1 highlighted that this signaling is required not only for autophagy but also for the triggering of early differentiation. In contrast, the extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway did not appear to be involved in the two processes, and AKT signaling, whose activation contributes to the FGFR2b-mediated onset of keratinocyte differentiation, was not required for the triggering of autophagy. Overall, our results point to JNK1 as a signaling hub that regulates the interplay between FGFR2b-induced autophagy and differentiation.

8The C-Terminal Kinase Domain-Binding and Suppression Motif Prevents Constitutive Activation of FGFR2.PubMed

Daniel Zingg, Chi-Chuan Lin, Julia Yemelyanenko, et al.
Cancer Res. 2025 Sep 2;85(17):3234-3257. doi: 10.1158/0008-5472.CAN-24-3349.
UNLABELLED: Genetic alterations in receptor tyrosine kinase genes can generate potent oncogenic drivers. Truncation of the FGFR2 gene by its last exon 18 (E18) is caused by structural alterations, such as focal amplifications and gene fusions/rearrangements, as well as by mutations. All the E18-truncating FGFR2 variants (FGFR2ΔE18) act as strong driver alterations in cancer, and they commonly encode a receptor lacking the carboxy (C) terminal tail. In this study, we analyzed a compendium of Fgfr2-E18 variants to uncover the mechanism by which loss of the C-tail renders FGFR2 oncogenic. Although permutation of previously annotated C-terminal FGFR motifs did not recapitulate the tumorigenicity of FGFR2ΔE18, the functional annotation efforts led to the discovery of a C-terminal phenylalanine-serine motif that mediates binding of the C-tail to the kinase domain and thereby suppresses FGFR2 kinase activity. The permutation of this kinase domain-binding and suppression motif in conjunction with other FGFR2-regulatory C-terminal sites fully phenocopied the oncogenic competence of FGFR2ΔE18. Together, these findings delineate how the C-terminal tail prevents FGFR2 from aberrant oncogenic activation. SIGNIFICANCE: A C-terminal phenylalanine-serine motif suppresses FGFR2 kinase activity by mediating binding of the C-terminal tail to the kinase domain, explaining how C-terminal truncation activates FGFR2 to promote tumorigenesis.

9Different clinical significance of FGFR1-4 expression between diffuse-type and intestinal-type gastric cancer.PubMed

Mikito Inokuchi, Hideaki Murase, Sho Otsuki, et al.
World J Surg Oncol. 2017 Jan 5;15(1):2. doi: 10.1186/s12957-016-1081-4.
BACKGROUND: Receptor tyrosine kinases promote tumor progression in many cancers, although oncologic activation differs between diffuse-type gastric cancer (DGC) and intestinal-type gastric cancer (IGC). Fibroblast growth factor receptor (FGFR) is one RTK, and we previously reported the clinical significance of FGFR1, 2, 3, and 4 in gastric cancer. The aim of the present study was to reevaluate the clinical significance of FGFR1-4 expression separately in DGC and IGC. METHODS: Tumor samples, including 109 DGCs and 100 IGCs, were obtained from patients who underwent gastrectomy between 2003 and 2007 in our institution. The expression levels of FGFR1, 2, 3, and 4 were measured in the tumors by immunohistochemical analysis. RESULTS: In DGC, high expression of FGFR1, FGFR2, or FGFR4 was significantly associated with the depth of invasion, lymph-node metastasis, pathological stage, and distant metastasis or recurrent disease. Patients with high expression of FGFR1, FGFR2, or FGFR4 had significantly poorer disease-specific survival (DSS) (p = 0.009, p = 0.001, and p = 0.023, respectively). In IGC, only FGFR4 expression was significantly associated with factors relative to tumor progression and with shorter DSS (p = 0.012). CONCLUSION: In conclusion, high FGFR4 expression correlated with tumor progression and survival in both DGC and IGC, whereas high expression of FGFR1 and 2 correlated with tumor progression and survival in only DGC.

10Evaluation of Fibroblast Growth Factor Receptor 2 Expression, Heterogeneity and Clinical Significance in Gastric Cancer.PubMed

Nayoung Han, Min A Kim, Hye Seung Lee, et al.
Pathobiology. 2015;82(6):269-79. doi: 10.1159/000441149. Epub 2015 Oct 31.
BACKGROUND: We aimed to evaluate the protein and mRNA expression of fibroblast growth factor receptor 2 (FGFR2) by immunohistochemistry (IHC) and mRNA in situ hybridization (ISH), respectively, and to assess the heterogeneity of FGFR2 expression in gastric cancer (GC). METHODS: A tissue microarray containing 362 surgically resected GC tissues and 135 matched metastatic lymph nodes was evaluated using FGFR2b IHC and FGFR2 ISH. FGFR2 fluorescence ISH was also performed in 188 cases. RESULTS: All FGFR2-amplified cases (5 of 188) showed FGFR2b protein and FGFR2 mRNA overexpression (p < 0.001), and FGFR2 amplification was not identified in FGFR2b IHC- and FGFR2 mRNA ISH-negative cases. Kaplan-Meier survival analysis revealed that FGFR2b protein and FGFR2 mRNA overexpression was significantly associated with a poor overall survival (p < 0.001 and p = 0.012, respectively), and multivariate analyses showed that FGFR2 mRNA overexpression was an independent biomarker of a poor overall survival. Intratumoral heterogeneity of FGFR2b protein and FGFR2 mRNA overexpression was observed in 5 of 9 (55.5%) and 18 of 21 (85.7%) cases, respectively. Discordant FGFR2b and FGFR2 expression results between primary and matched metastatic lymph nodes were observed in 5 of 9 (55.5%) and 4 of 14 (28.6%) cases, respectively. CONCLUSIONS: Intratumoral heterogeneity and discordant FGFR2b expression in primary tumors and metastatic lymph nodes are common in GC.

11Prevalence of FGFR2b Protein Overexpression in Advanced Gastric Cancers During Prescreening for the Phase III FORTITUDE-101 Trial.PubMed

Sun Young Rha, Yanqiao Zhang, Anneli Elme, et al.
JCO Precis Oncol. 2025 Jan;9:e2400710. doi: 10.1200/PO-24-00710. Epub 2025 Jan 24.
PURPOSE: Fibroblast growth factor receptor 2 isoform IIIb (FGFR2b) protein overexpression is an emerging biomarker in gastric cancer and gastroesophageal junction cancer (GC). We assessed FGFR2b protein overexpression prevalence in nearly 3,800 tumor samples as part of the prescreening process for a global phase III study in patients with newly diagnosed advanced or metastatic GC. METHODS: As of June 28, 2024, 3,782 tumor samples from prescreened patients from 37 countries for the phase III FORTITUDE-101 trial (ClinicalTrials.gov identifier: NCT05052801) were centrally tested for FGFR2b protein overexpression by immunohistochemistry (IHC) and had evaluable results. FGFR2b positivity was defined as both any % tumor cells (TC) and ≥10% TC exhibiting moderate-to-strong (2+/3+) membranous FGFR2b staining. Prevalence was analyzed across patient and sample characteristics. RESULTS: FGFR2b protein overexpression at any % and ≥10%, 2+/3+ TC positivity was 37.8% (1,428/3,782 [95% CI, 36.2 to 39.3]) and 16.2% (612/3,782 [95% CI, 15 to 17.4]), respectively. Of any %, 2+/3+ TC-positive tumors, 42.9% (612/1,428 [95% CI, 40.3 to 45.4]) were FGFR2b ≥10%, 2+/3+ TC positive. FGFR2b prevalence was not notably different within multiple patient and sample characteristics examined (age, sex, collection method [biopsy resection], collection site, location of primary tumor, and geographic region). CONCLUSION: As of the data cutoff date, we report the largest prevalence assessment of FGFR2b protein overexpression in GC with more than one third (37.8%) of patients with GC exhibiting FGFR2b protein overexpression (any % TC, 2+/3+) by a validated IHC assay. Approximately 16% of patients had FGFR2b protein overexpression in ≥10% of TC. FGFR2b prevalence was similar across geographic regions and within defined patient and sample variables regardless of the level of expression.

12Clinical characterization of FGFR2b expression in patients with advanced gastric or gastroesophageal junction adenocarcinoma.PubMed

S Sato, S L Rhodes, Y Aoki, et al.
ESMO Open. 2025 Jul;10(7):105322. doi: 10.1016/j.esmoop.2025.105322. Epub 2025 Jun 12.
BACKGROUND: Fibroblast growth factor receptor 2b (FGFR2b) is a novel protein biomarker expressed in gastric and gastroesophageal junction tumors (GC/GEJC). Phase III trials are evaluating the efficacy and safety of FGFR2b-targeting therapies. However, features of FGFR2b-expressing tumors and co-occurrence of FGFR2b expression with currently actionable biomarkers in gastric cancer remain unclear. MATERIALS AND METHODS: We carried out a single-institution retrospective cohort study of patients who initiated systemic therapy for GC/GEJC to evaluate features of FGFR2b-positive tumors, first-line (1L) treatments received, and co-occurrence with select actionable biomarkers [human epidermal growth factor receptor 2 (HER2), mismatch repair, programmed death-ligand 1 (PD-L1), claudin-18 isoform 2]. A sample was deemed FGFR2b-positive when any (>0%) tumor cells exhibiting moderate (2+) or strong (3+) membrane staining were detected ('any 2+/3+'). Other biomarkers were assessed based on current clinical guidelines. FGFR2b-stratified real-world overall survival (OS) was estimated using the Kaplan-Meier and Cox proportional regression models. RESULTS: Of 547 GC/GEJC patients identified, 492 (89.9%) met inclusion/exclusion criteria, had evaluable FGFR2b staining, and had complete clinical data. Estimated prevalence of FGFR2b any 2+/3+ was 15.4% [95% confidence interval (CI) 12.4% to 19.0%] in the full cohort of patients and 29.8% (95% CI 22.0% to 38.7%) in patients with samples collected within 1.5 years of study initiation. The majority (53.9%; 95% CI 42.1% to 65.5%) of FGFR2b any 2+/3+ tumor specimens were negative for other assessed biomarkers at a PD-L1 cut-off of combined positive score ≥5. In HER2-negative patients treated in 1L with chemotherapy alone, median OS was 11.5 months (95% CI 10.0-16.3 months) and 15.3 months (95% CI 13.0-16.8 months) for FGFR2b any 2+/3+ and FGFR2b 0/1+, respectively. There was no association between FGFR2b overexpression level and OS [adjusted hazard ratio (HR) 1.14, 95% CI 0.84-1.55]. CONCLUSIONS: This study revealed limited overlap of FGFR2b overexpression with currently actionable biomarkers, suggesting FGFR2b is a novel biomarker that identifies a distinct GC/GEJC patient population who may benefit most from an FGFR2b-targeting therapy.

13FGFR2 in gastric cancer: protein overexpression predicts gene amplification and high H-index predicts poor survival.PubMed

Soomin Ahn, Jeeyun Lee, Mineui Hong, et al.
Mod Pathol. 2016 Sep;29(9):1095-103. doi: 10.1038/modpathol.2016.96. Epub 2016 May 27.
FGFR2 gene amplification, and resulting FGFR2 protein overexpression, is rare in gastric cancer patients, and development of an accurate and widely available method for mass screening to identify patients who may respond to treatment with fibroblast growth factor receptor (FGFR) inhibitors is important. We first screened 312 gastric cancer patients with known copy number variations by FGFR2b immunohistochemistry using FPR2-D, an isoform-specific antibody. Next, we performed immunohistochemistry on tissue microarrays from 1574 gastric cancer patients. Selected cases were analyzed for FGFR2 amplification by FISH. In addition, FGFR2b overexpression was studied in 88 matched primary and metastatic gastric cancers. In the first cohort, FGFR2b immunohistochemistry results correlated very well with those of copy number variation (r=0.79) and FISH (r=1.0). In total, FGFR2b overexpression was identified in 73 of 1974 gastric cancers (4%). The concordance between immunohistochemistry and FISH was extremely high; all 2+ and 3+ cases identified by immunohistochemistry were FGFR2 amplified. In the matched primary and metastatic gastric cancer pairs, the positivity and percentage of positive tumor cells were significantly higher in metastatic gastric cancers than in primary gastric cancers (8% vs 3% and 75% vs 47%, respectively; P<0.001). FGFR2b overexpression was significantly more frequent in gastric cancers with diffuse subtype (P=0.01) and higher N stage (P=0.006). FGFR2b overexpression with H-score ≥150 were independent prognostic factors for overall survival with hazard ratio of 1.836 (95% confidence interval, 1.034-3.261; P=0.038). FGFR2b positivity in immunohistochemistry was strongly correlated with FGFR2 amplification. Given the low frequency of FGFR2 amplification in gastric cancers, FGFRb2 immunohistochemistry is an accurate screening tool to detect FGFR2 amplification, and both primary and metastatic gastric cancer tissues should be tested to select gastric cancer patients for treatment with FGFR2 inhibitors.

14In situ analysis of FGFR2 mRNA and comparison with FGFR2 gene copy number by dual-color in situ hybridization in a large cohort of gastric cancer patients.PubMed

Yasutoshi Kuboki, Christoph A Schatz, Karl Koechert, et al.
Gastric Cancer. 2018 May;21(3):401-412. doi: 10.1007/s10120-017-0758-x. Epub 2017 Aug 29.
BACKGROUND: Fibroblast growth factor receptor (FGFR2) has been proposed as a target in gastric cancer. However, appropriate methods to select patients for anti-FGFR2 therapies have not yet been established. METHODS: We used in situ techniques to investigate FGFR2 mRNA expression and gene amplification in a large cohort of 1036 Japanese gastric cancer patients. FGFR2 mRNA expression was determined by RNAscope. FGFR2 gene amplification was determined by dual-color in situ hybridization (DISH). RESULTS: We successfully analyzed 578 and 718 samples by DISH and RNAscope, respectively; 2% (12/578) showed strong FGFR2 gene amplification (FGFR2:CEN10 >10); moderate FGFR2 gene amplification (FGFR2:CEN10 <10; ≥2) was detected in 8% (47/578); and high FGFR2 mRNA expression of score 4 (>10 dots/cell and >10% of positive cells with dot clusters under a 20× objective) was seen in 4% (29/718). For 468 samples, both mRNA and DISH data were available. FGFR2 mRNA expression levels were associated with gene amplification; FGFR2 mRNA levels were highest in the highly amplified samples (n = 12). All highly amplified samples showed very strong FGFR2 mRNA expression (dense clusters of the signal visible under a 1× objective). Patients with very strong FGFR2 mRNA expression showed more homogeneous FGFR2 mRNA expression compared to patients with lower FGFGR2 mRNA expression. Gastric cancer patients with tumors that had an FGFR2 mRNA expression score of 4 had shorter RFS compared with score 0-3 patients. CONCLUSION: RNAscope and DISH are suitable methods to evaluate FGFR2 status in gastric cancer. Formalin-fixed paraffin-embedded (FFPE) tissue slides allowed evaluation of the intratumor heterogeneity of these FGFR2 biomarkers.

15Clinical difference between fibroblast growth factor receptor 2 subclass, type IIIb and type IIIc, in gastric cancer.PubMed

Masakazu Yashiro, Kenji Kuroda, Go Masuda, et al.
Sci Rep. 2021 Feb 25;11(1):4698. doi: 10.1038/s41598-021-84107-x.
Fibroblast growth factor receptor 2 (FGFR2) has two isoforms: IIIb type and IIIc type. Clinicopathologic significance of these two FGFR2 subtypes in gastric cancer remains to be known. This study aimed to clarify the clinicopathologic difference of FGFR2IIIb and/or FGFR2IIIc overexpression. A total of 562 patients who underwent gastrectomy was enrolled. The expressions of FGFR2IIIb and FGFR2IIIc were retrospectively examined by immunohistochemistry or fluorescence in situ hybridization (FISH) using the 562 gastric tumors. We evaluated the correlation between clinicopathologic features and FGFR2IIIb overexpression and/or FGFR2IIIc overexpression in gastric cancer. FGFR2IIIb overexpression was observed in 28 cases (4.9%), and FGFR2IIIc overexpression was observed in four cases (0.7%). All four FGFR2IIIc cases were also positive for FGFR2IIIb, but not in the same cancer cells. FGFR2IIIb and/or FGFR2IIIc overexpression was significantly correlated with lymph node metastasis and clinical stage. Both FGFR2IIIb and FGFR2IIIc were significantly associated with poor overall survival. A multivariate analysis showed that FGFR2IIIc expression was significantly correlated with overall survival. FISH analysis indicated that FGFR2 amplification was correlated with FGFR2IIIb and/or FGFR2IIIc overexpression. These findings suggested that gastric tumor overexpressed FGFR2IIIc and/or FGFR2IIIb at the frequency of 4.9%. FGFR2IIIc overexpression might be independent prognostic factor for patients with gastric cancer.

16FGFR2 overexpression and compromised survival in diffuse-type gastric cancer in a large central European cohort.PubMed

Thorben Schrumpf, Hans-Michael Behrens, Jochen Haag, et al.
PLoS One. 2022 Feb 15;17(2):e0264011. doi: 10.1371/journal.pone.0264011. eCollection 2022.
The significance of fibroblast growth factor receptor 2 (FGFR2) in gastric cancer (GC) has been studied predominantly in Asian patient cohorts. Data on White patients are scarce. Here, we aimed to independently validate the expression and putative tumor biological significance of FGFR2 in a large non-Asian GC cohort. Immunohistochemistry (IHC) was performed on large-area tissue sections from 493 patients with GC and evaluated using the HScore. GCs with moderate and strong FGFR2 expression were studied for Fgfr2 amplification using chromogenic in situ hybridization (CISH). Median overall survival was determined using the Kaplan-Meier method. The majority [240 (99.1%)] of FGFR2-positive GCs showed a variable combination of staining intensities with marked intratumoral heterogeneity, including weak [198 (40.2%) cases], moderate [145 (29.4%)], and strong [108 (21.9%)] staining in diverse combinations. 250 (50.9%) GCs expressed no FGFR2. Fgfr2 gene amplification was found in 40% of selected cases with high protein expression and was also heterogeneous at the cell level. FGFR2 protein expression did not correlate with patient survival in the entire cohort However, using different cutoff values, a negative correlation between FGFR2-expression and patient outcome was found for diffuse-type GC. FGFR2 expression was associated with a lower tumor grade and intestinal phenotype (p≤0.0001). FGFR2-positive diffuse-type GCs classify a small subset of patients with a poor tumor specific survival (5.29±1.3 vs. 14.67±1.9 months; p = 0.004).

17Correlation and Overlap Between Claudin 18.2 and FGFR2b Overexpression: A Tissue Microarray Study With 1,538 Gastric Carcinomas.PubMed

Soomin Ahn, Inwoo Hwang, Kyoung-Mee Kim
J Gastric Cancer. 2025 Oct;25(4):639-650. doi: 10.5230/jgc.2025.25.e47.
PURPOSE: Claudin 18.2 (CLDN18.2) and fibroblast growth factor receptor 2b (FGFR2b) have recently emerged as promising therapeutic targets for advanced gastric cancer (GC). Before integrating CLDN18.2 and FGFR2b into routine practice, for optimal treatment planning, it is important to consider whether there exists an overlap between these biomarkers. MATERIALS AND METHODS: We evaluated CLDN18.2 expression in many patients with GC (n=1,538) using tissue microarrays that had been previously used to evaluate FGFR2b overexpression. We investigated the overlap between CLDN18.2 and FGFR2b expression and evaluated the clinicopathological features and prognostic implications of CLDN18.2 expression. RESULTS: The CLDN18.2 positivity rates at 50% and 75% cutoffs were 34.7% and 24.4%, respectively. Heterogeneous expression was identified in 335 (23.5%) of 1426 cases with multiple tissue microarray cores. FGFR2b positivity at >0% cutoff was identified in 47 (3.1%) patients with more marked intratumoral heterogeneity than that observed with CLDN18.2. CLDN18.2 positivity (59.6%) in FGFR2b-positive GCs was significantly higher than that (33.9%) in FGFR2b-negative GCs (P<0.001). Concurrent FGFR2b- and CLDN18.2-positive GCs accounted for 1.8% of all patients, and FGFR2b-positive tumor cells were also positive for CLDN18.2 in approximately 75% of these cases. CLDN18.2 positivity was associated with poorly differentiated histology (P<0.001) and advanced pT and pN stages (P<0.03), but not with overall survival. CONCLUSIONS: CLDN18.2 and FGFR2b were significantly associated with each other, suggesting a considerable overlap. This finding may have important clinical implications on the optimal treatment strategy for CLDN18.2-positive GC.

18FGFR2-amplified tumor clones are markedly heterogeneously distributed in carcinomas of the upper gastrointestinal tract.PubMed

Jan Albin, Luca Fahrig, Janna Siemanowski, et al.
J Cancer Res Clin Oncol. 2023 Jul;149(8):5289-5300. doi: 10.1007/s00432-022-04460-w. Epub 2022 Nov 23.
BACKGROUND: FGFR2 is a therapy-relevant target in tumors of the upper gastrointestinal tract (GIT), and clinical trials are currently underway to test the efficacy of FGFR2 inhibitors. Tumor heterogeneity is one of the relevant causes of treatment failure. Almost nothing is known about the heterogeneous distribution of FGFR2-amplified clones in adenocarcinomas of the upper GIT. PATIENTS AND METHODS: To assess FGFR2 gene copy number alteration and intratumoral heterogeneity of upper GIT adenocarcinomas, we analyzed 893 patient-derived formalin-fixed paraffin-embedded tumor specimens, including primary operated and neoadjuvant-treated tumors (462 gastric carcinomas and 429 esophageal adenocarcinomas) as well as complementary lymph node and distant metastasis by fluorescence in situ hybridization. RESULTS: Twenty-six gastric tumors (5.6%) and 21 esophageal adenocarcinomas (4.9%) showed FGFR2 amplification. Overall, 93% of gastric carcinomas and 83% of esophageal carcinomas showed heterogeneous amplification. FGFR2 amplification was found in different histological growth patterns, including intestinal and diffuse type according to the Lauren classification. In the primary gastric carcinoma group, FGFR2 amplification was associated with poor prognosis (p = 0.005). CONCLUSION: Homogeneous FGFR2 amplification in tumors of the upper GIT is the exception. This has highly relevant implications in the nature of FGFR2 diagnostics (sufficient tumor cell number, determination of amplification at metastasis versus primary tumor, etc.) and on the response probability of appropriate inhibitors. It is relevant that the often poorly treatable and aggressive subtype of diffuse carcinomas (poorly cohesive carcinomas) also shows FGFR2 amplification and that an individualized therapy option with FGFR2 inhibitors could be an option in this group.

19A randomized, open-label study of the efficacy and safety of AZD4547 monotherapy versus paclitaxel for the treatment of advanced gastric adenocarcinoma with FGFR2 polysomy or gene amplification.PubMed

E Van Cutsem, Y-J Bang, W Mansoor, et al.
Ann Oncol. 2017 Jun 1;28(6):1316-1324. doi: 10.1093/annonc/mdx107.
BACKGROUND: Approximately 5%-10% of gastric cancers have a fibroblast growth factor receptor-2 (FGFR2) gene amplification. AZD4547 is a selective FGFR-1, 2, 3 tyrosine kinase inhibitor with potent preclinical activity in FGFR2 amplified gastric adenocarcinoma SNU16 and SGC083 xenograft models. The randomized phase II SHINE study (NCT01457846) investigated whether AZD4547 improves clinical outcome versus paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma displaying FGFR2 polysomy or gene amplification detected by fluorescence in situ hybridization. PATIENTS AND METHODS: Patients were randomized 3:2 (FGFR2 gene amplification) or 1:1 (FGFR2 polysomy) to AZD4547 or paclitaxel. Patients received AZD4547 80 mg twice daily, orally, on a 2 weeks on/1 week off schedule of a 21-day cycle or intravenous paclitaxel 80 mg/m2 administered weekly on days 1, 8, and 15 of a 28-day cycle. The primary end point was progression-free survival (PFS). Safety outcomes were assessed and an exploratory biomarker analysis was undertaken. RESULTS: Of 71 patients randomized (AZD4547 n = 41, paclitaxel n = 30), 67 received study treatment (AZD4547 n = 40, paclitaxel n = 27). Among all randomized patients, median PFS was 1.8 months with AZD4547 and 3.5 months with paclitaxel (one-sided P = 0.9581); median follow-up duration for PFS was 1.77 and 2.12 months, respectively. The incidence of adverse events was similar in both treatment arms. Exploratory biomarker analyses revealed marked intratumor heterogeneity of FGFR2 amplification and poor concordance between amplification/polysomy and FGFR2 mRNA expression. CONCLUSIONS: AZD4547 did not significantly improve PFS versus paclitaxel in gastric cancer FGFR2 amplification/polysomy patients. Considerable intratumor heterogeneity for FGFR2 gene amplification and poor concordance between FGFR2 amplification/polysomy and FGFR2 expression indicates the need for alternative predictive biomarker testing. AZD4547 was generally well tolerated.

20Spatial heterogeneity of FGFR2b in gastric cancer: a comparative analysis of primary tumors and peritoneal dissemination.PubMed

Haruki Ogawa, Hiroyuki Abe, Koichi Yagi, et al.
Virchows Arch. 2025 Aug 30. doi: 10.1007/s00428-025-04233-z.
Gastric cancer with peritoneal dissemination (PD) confers poor prognosis and limited treatment options. FGFR2b-targeted therapy has emerged as a potential approach for FGFR2b-positive tumors. However, the expression and amplification status of FGFR2b in PD remains poorly characterized. This study aimed to investigate FGFR2b expression and gene amplification in matched primary tumors and PD tissues from gastric cancer patients, and to evaluate their association with established biomarkers including HER2, CLDN18, and PD-L1. Immunohistochemistry (IHC) for FGFR2b was performed on matched primary and PD tissues from 84 patients. FGFR2 FISH was conducted in IHC-positive cases. FGFR2b expression was detected in 7.1% (6/84) of primary tumors and 4.8% (4/84) of PD samples. Expression was highly heterogeneous; only one case was FGFR2b-positive in both primary and PD tissues. FGFR2 amplification was found in 6 of 10 IHC-positive samples, and not observed in IHC-negative samples. FGFR2b status showed no significant correlation with HER2, CLDN18, or PD-L1. FGFR2b expression in gastric cancer is spatially heterogeneous and discordant between primary tumors and PD. It may be preferable to test both primary tumor and PD tissue, if available, to better identify candidates for FGFR2b-targeted therapy. FGFR2b represents a potential therapeutic target for a subset of PD-positive gastric cancers lacking other biomarker expression.

21Association between FGFR2b Positivity and Survival Outcomes of Patients with Gastric Cancer Treated with First-Line Nivolumab Plus Chemotherapy.PubMed

Hyung-Don Kim, Heonwoo Lee, Hyungeun Lee, et al.
Cancer Res Treat. 2025 Nov 24. doi: 10.4143/crt.2025.598.
PURPOSE: Fibroblast growth factor receptor 2b (FGFR2b) is a promising therapeutic target in gastric cancer; however, its clinical relevance in immune checkpoint inhibitor (ICI)-based chemotherapy remains unclear. Therefore, this study aims to evaluate the expression pattern and predictive value of FGFR2b in patients undergoing first-line nivolumab plus chemotherapy. MATERIALS AND METHODS: This single-center study included 503 patients diagnosed with gastric cancer. Among them, 296 underwent nivolumab-chemotherapy, while 207 underwent chemotherapy alone. FGFR2b expression was assessed via immunohistochemistry using samples collected after mid-2022. FGFR2b positivity was defined as membranous staining intensity of 2+/3+ in ≥ 1% of tumor cells, with ≥ 10% as overexpression, and 1-9% as low expression. RESULTS: FGFR2b overexpression and positivity were identified in 9.3% and 18.7% of cases, respectively. Discordance between paired biopsy and surgical samples was observed (20.0% and 40.0% for overexpression and positivity, respectively), indicating marked intratumoral heterogeneity. Among patients who underwent nivolumab-chemotherapy, FGFR2b overexpression and low expression were associated with favorable survival trends compared to those of FGFR2b-negative cases. These associations were not observed in patients treated with chemotherapy alone. Compared to chemotherapy alone, nivolumab-chemotherapy was associated with a greater survival benefit in patients with FGFR2b positivity. Multivariate interaction analyses revealed a significant interaction between FGFR2b expression and nivolumab-based chemotherapy. CONCLUSION: FGFR2b expression exhibits substantial intratumoral heterogeneity in gastric cancer and may be linked to favorable outcomes in patients undergoing first-line ICI plus chemotherapy. Therefore, future studies should validate this finding, along with mechanistic investigations.

22Prognostic impact of fibroblast growth factor receptor 2 gene amplification in patients receiving fluoropyrimidine and platinum chemotherapy for metastatic and locally advanced unresectable gastric cancers.PubMed

Seyoung Seo, Seong Joon Park, Min-Hee Ryu, et al.
Oncotarget. 2017 May 16;8(20):33844-33854. doi: 10.18632/oncotarget.12953.
Although Fibroblast growth factor receptor (FGFR) 2 gene amplification and its prognostic significance have been reported in resectable gastric cancers, information on these features remains limited in the metastatic setting. The presence of FGFR2 amplification was assessed in formalin-fixed, paraffin-embedded tissues using a quantitative PCR-based gene copy number assay with advanced gastric cancer cohorts. A total of 327 patients with tumor portion of ≥70% were analyzed for clinical features. Among these patients, 260 who received first-line fluoropyrimidine and platinum chemotherapy were analyzed for survival.Sixteen of 327 patients (4.9%) exhibited FGFR2 amplification. The amplification group showed associations with age <65 years, Borrmann type 4 disease, poor performance status, poorly differentiated histology, extra-abdominal lymph node metastases, and bone metastases. The median overall survival (OS) and progression-free survival (PFS) were found to be 12.7 and 5.8 months, respectively. In univariate analysis, PFS did not differ between amplification and no amplification groups (hazard ratio [HR]=1.34, 95% confidence interval [CI]: 0.78-2.31, p=0.290), although the OS was significantly shorter in the amplification group (HR=1.92, 95% CI: 1.13-3.26, p=0.015). However, multivariate analysis indicated that FGFR2 amplification was not an independent prognostic factor for OS (HR=1.42, 95% CI: 0.77-2.61, p=0.261).Although FGFR2 amplification is associated with poorer OS, it does not appear to be an independent prognostic predictor in patients with advanced gastric cancer treated with palliative fluoropyrimidine and platinum chemotherapy.

23High-level FGFR2 amplification is associated with poor prognosis and Lower response to chemotherapy in gastric cancers.PubMed

Joon Young Hur, Joseph Chao, Kyung Kim, et al.
Pathol Res Pract. 2020 Apr;216(4):152878. doi: 10.1016/j.prp.2020.152878. Epub 2020 Feb 13.
BACKGROUND: Recurrent FGFR2 amplification is observed in gastroesophageal cancers but clinical implications are unknown. We investigated the association of FGFR2 amplification with cytotoxic chemotherapy outcome in gastroesophageal cancer (GC) patients. METHODS: Between 2016 and 2018, we identified 1045 metastatic GC patients who received palliative fluoropyrimidine/platinum-based chemotherapy and underwent tumor genomic profiling at a tertiary hospital in Korea and two US cancer centers. We retrospectively identified FGFR2-amplified cases and abstracted clinicopathologic features and treatment outcomes. Cox proportional hazard regression model was used to evaluate the variables that demonstrated effects on progression free and overall survival PFS and OS. Descriptive statistics were used to correlate level of FGFR2 copy number amplification CNA and clinicopathological parameters. RESULTS: The incidence of FGFR2-amplified GC was 4.0 %. A total of 42 FGFR2-amplified GC patients were included and divided into high and lower FGFR2 amplification values. Fifteen patients had an FGFR2 CNA greater than 30, and 27 had a CNA of 30 or less. There was no significant differences between age, sex, tumor localization, Lauren classification, or tumor staging. After a median follow-up duration of 11.4 months, patients with high FGFR2 amplification had significantly poorer median PFS (3.2 vs. 4.8 months, hazard ratio (HR) 2.08, 95 % CI, 1.03-4.22, P = 0.042) and significantly shorter median OS (10.1 vs. 26.3 months, HR 2.99, 95 % CI = 1.05-8.49, P = 0.040) than the low FGFR2 amplification group. CONCLUSION: Recurrent FGFR2 amplification was observed in roughly 4.0 % of GC patients. High FGFR2 amplification was significantly associated with poor progression free survival and overall survival in GC patients. Clinical studies of FGFR2-directed therapies are warranted and should consider stratification by FGFR2 CNA.

24Deciphering the FGFR2 Code: Innovative Targets in Gastric Cancer Therapy.PubMed

Alireza Tojjari, Sarbajeet Nagdas, Ali Saeed, et al.
Curr Oncol. 2024 Jul 29;31(8):4305-4317. doi: 10.3390/curroncol31080321.
Gastric cancer (GC) represents a major global health challenge as a highly prevalent disease with high mortality whose global incidence and mortality are predicted to worsen over the coming years. To date, our standard of care for advanced gastric cancer of combination chemotherapy and immunotherapy has a 1-year overall survival rate of 55%. Significant efforts have gone into identifying targetable alterations in gastric cancer, ultimately yielding the Fibroblast Growth Factor Receptors (FGFRs) family, specifically FGFR2 as a promising target. FGFR2 is overexpressed in GC, particularly diffuse-type GC, and is associated with poor prognostic outcomes. In recent years, there has been an increasing number of small molecule inhibitors and monoclonal antibodies targeting FGFR2 that have entered into clinical trials. Specifically for GC, these agents are currently being trialed in various phases as monotherapies or with standard-of-care treatments to make a clinically meaningful impact on what appears to be an important biological axis of GC. In this review, we outline the underlying biology of FGFR2, its putative role in GC, and the various FGFR2-targeted agents currently in clinical trials for gastric cancer patients as well as postulate some challenges in adopting these therapeutics for clinically meaningful benefit.

25FGFR2-IIIc isoform detection reveals prognostic prevalence and a functional link to mesenchymal transition in gastric and gastroesophageal junction cancer.PubMed

T Hashimoto, N Iida, S Kadowaki, et al.
ESMO Open. 2025 Nov;10(11):105851. doi: 10.1016/j.esmoop.2025.105851. Epub 2025 Oct 30.
BACKGROUND: Fibroblast growth factor receptor 2 (FGFR2), a therapeutic target for advanced gastric and gastroesophageal junction cancers (GC/GEJCs), exists as two functionally distinct isoforms: FGFR2-IIIb and FGFR2-IIIc. We investigated the clinical significance of FGFR2 splice variant distribution in advanced GC/GEJCs and its implications for therapeutic targeting. PATIENTS AND METHODS: Whole-transcriptome sequencing was carried out on 235 patients with advanced GC/GEJCs enrolled in MONSTAR-SCREEN-2 (UMIN000043899). FGFR2-IIIc proportion was quantified using splice junction analysis, and its association with clinical outcomes was evaluated through survival analysis, comprehensive molecular profiling, and longitudinal assessment of treatment-induced isoform dynamics. RESULTS: Among 209 patients with detectable FGFR2 expression, high-proportion FGFR2-IIIc (>0.28) was associated with significantly shorter overall survival compared with low-proportion FGFR2-IIIc (median 9.59 versus 16.0 months, hazard ratio 2.08, 95% confidence interval 1.33-3.26, P < 0.001). Multivariable Cox regression confirmed FGFR2-IIIc proportion as an independent predictor of poor prognosis (P = 0.008), superior to total FGFR2 expression levels. Longitudinal analysis of 33 paired pre- and post-treatment samples revealed treatment-induced increases in FGFR2-IIIc proportion (P = 0.0085), suggesting adaptive isoform switching. Notably, all tumors with elevated FGFR2 expression exclusively belonged to the low-IIIc group, indicating that current FGFR2-targeted therapies primarily benefit patients with FGFR2-IIIb-dominant expression profiles. High-proportion FGFR2-IIIc was significantly associated with epithelial-to-mesenchymal transition and myogenesis pathway activation. Differential splicing analysis identified coordinated alternative splicing events in ESRP1-regulated targets, suggesting potential broader splicing dysregulation and providing mechanistic insights into the aggressive phenotype. CONCLUSIONS: FGFR2-IIIc proportion represents a clinically relevant prognostic biomarker in advanced GC/GEJCs. Treatment-induced isoform switching toward FGFR2-IIIc suggests a novel resistance mechanism requiring targeted therapeutic approaches. These findings underscore the importance of developing isoform-specific therapeutic strategies and implementing FGFR2-IIIc assessment in precision oncology approaches for GC/GEJCs.

26Targeting the fibroblast growth factor receptor 2 in gastric cancer: promise or pitfall?PubMed

C Hierro, M Alsina, M Sánchez, et al.
Ann Oncol. 2017 Jun 1;28(6):1207-1216. doi: 10.1093/annonc/mdx081.
Gastric cancer is the third leading cause of death from cancer worldwide. Systemic chemotherapy remains the mainstay therapeutic option for this poor prognosis cancer. Trastuzumab, the epidermal growth factor receptor 2 (ERBB2 or HER2)-antibody, is the only biological agent approved for the molecularly selected population of HER2-positive gastric cancer patients. Over the last decade, several groups have been working for deepening into the molecular characterization of gastric cancer, shedding some light into the heterogeneity of this tumour. The published data have broadened the landscape towards a future molecular classification into several subtypes of gastric cancer, enabling a better selection of the optimal therapeutic strategy. The fibroblast growth factor receptor (FGFR) pathway plays a key role in gastric cancer pathogenesis, with 1.2%-9% of gastric cancer patients harbouring FGFR2 amplifications. Several selective FGFR inhibitors have been developed in the last years, with promising efficacy signals. However, there is still scarce evidence of the most reliant molecular determinants of response to these targeted agents. Homogeneous high-level clonal FGFR2-amplification, high FGFR2 mRNA or protein levels, specific FGFR2 C3 isoform expression, FGF ligand co-overexpression or detection of FGFR2 copy number in plasma circulating tumour DNA, are considered some of the potential predictive biomarkers to the FGFR inhibition. The successful development of highly specific FGFR inhibitors will rely on our capacity of establishing new personalized strategies, based on a deeper knowledge of the key alterations that drive oncogenesis in gastric cancer. Further efforts seem mandatory in order to implement accurate predictive biomarkers in the next stages of the FGFR inhibitors development.

27Immunotherapy and targeted therapy as first-line treatment for advanced gastric cancer.PubMed

Guocheng Wang, Yan Huang, Liang Zhou, et al.
Crit Rev Oncol Hematol. 2024 Jun;198:104197. doi: 10.1016/j.critrevonc.2023.104197. Epub 2023 Nov 10.
For patients diagnosed with advanced gastric or gastroesophageal cancer that is not amenable to surgical intervention, the standard of care for first-line treatment consists of fluoropyrimidine and platinum-based chemotherapy. The incorporation of novel agents into these standard first-line regimens could potentially improve patient prognosis; options for such augmentations include both immune-based and targeted therapy combinations. To provide a comparative analysis of these different first-line combination treatments, a network meta-analysis was conducted. Outcome measures comprised overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and grade 3-4 treatment-related adverse events (TRAEs). Data were drawn from 22 randomized controlled trials, encompassing 10,787 patients and 17 distinct treatment regimens. Our findings suggest that FGFR2b-targeted therapy, specifically when used in combination with chemotherapy (bemarituzumab_chemo), exhibited the greatest efficacy. This was followed by immunotherapy-based combination regimens (CPS ≥5, Sintilimab_chemo). Further, targeted combination therapy featuring CLAUDIN 18.2 (zolbetuximab_chemo) appeared beneficial based on individual patient characteristics. In the case of HER2-positive patients, the trastuzumab_chemo regimen is recommended, as most existing studies have excluded this subpopulation. These results have significant implications for both clinical decision-making and patient care in the realm of advanced gastric or gastroesophageal cancer treatment.

28FGFR2b protein overexpression: An emerging biomarker in gastric and gastroesophageal junction adenocarcinoma.PubMed

Elizabeth C Smyth, Kyoung-Mee Kim, Sun Young Rha, et al.
Cancer Treat Rev. 2025 Sep;139:102971. doi: 10.1016/j.ctrv.2025.102971. Epub 2025 May 26.
Gastric and gastroesophageal junction cancer (G/GEJC) is a heterogeneous and complex disease characterized by histologic and molecular subtypes. Although a growing number of treatments have improved survival outcomes in the advanced setting, the greatest therapeutic benefits are observed among patient populations eligible for biomarker-directed therapies. Fibroblast growth factor receptor 2 isoform IIIb (FGFR2b) is an emerging biomarker under phase 3 clinical investigation for G/GEJC with the novel monoclonal antibody bemarituzumab. FGFR2b protein overexpression in gastric cancer, together with its function in various oncogenic signaling pathways, makes it an attractive target for precision medicine and thereby has gained clinical interest for its potential prognostic role in G/GEJC. Thus, to explore the potential role of FGFR2b, this narrative review summarizes the role and mechanism of FGFR2b in advanced G/GEJC, describes appropriate detection methodology for FGFR2b protein overexpression, and discusses future considerations for precision treatment in advanced G/GEJC with respect to FGFR2b protein overexpression and the emergence of other biomarkers.

29Bemarituzumab plus mFOLFOX6 as first-line treatment in East Asian patients with FGFR2b-overexpressing locally advanced or metastatic gastric/gastroesophageal junction cancer: subgroup of FIGHT final analysis.PubMed

Yoon-Koo Kang, Shukui Qin, Keun-Wook Lee, et al.
Gastric Cancer. 2024 Sep;27(5):1046-1057. doi: 10.1007/s10120-024-01516-3. Epub 2024 Jun 11.
BACKGROUND: In the FIGHT study (NCT03694522) bemarituzumab, a humanized monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b), plus mFOLFOX6 showed clinically meaningful efficacy in patients with FGFR2b-positive (2+/3+ membranous staining by immunohistochemistry) locally advanced unresectable/metastatic gastric/gastroesophageal cancer (G/GEJC). A meaningful proportion of patients in FIGHT were enrolled in East Asia, reflecting global epidemiology of G/GEJC. METHODS: This subgroup analysis of the global, phase 2, double-blind FIGHT study included all patients enrolled in East Asian sites. Patients were randomized 1:1 to bemarituzumab-mFOLFOX6 (15 mg/kg and one 7.5 mg/kg dose on cycle 1, day 8) or matching placebo-mFOLFOX6. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, and safety. Efficacy was evaluated after a minimum follow-up of 24 months. RESULTS: The East Asian subgroup comprised 89 patients (57% of overall study population); 45 were randomized to bemarituzumab-mFOLFOX6 and 44 to placebo-mFOLFOX6. Median PFS (95% confidence interval [CI]) was 12.9 months (8.8-17.9) with bemarituzumab-mFOLFOX6 and 8.2 months (5.6-10.3) with placebo-mFOLFOX6 (HR 0.50, 95% CI 0.29-0.87); median OS (95% CI) was 24.7 months (13.8-33.1) vs 12.9 months (9.3-21.4), respectively (HR 0.56, 95% CI 0.32-0.96). Treatment benefit was more pronounced in patients with FGFR2b-positive G/GEJC in ≥ 10% of tumor cells. No new safety signals were reported. CONCLUSION: In East Asian patients with FGFR2b-positive advanced/metastatic G/GEJC enrolled in the global FIGHT study, bemarituzumab-mFOLFOX6 showed clinically meaningful outcomes over placebo-mFOLFOX6.

30Preclinical characterization of bemarituzumab, an anti-FGFR2b antibody for the treatment of cancer.PubMed

Hong Xiang, Abigael G Chan, Ago Ahene, et al.
MAbs. 2021 Jan-Dec;13(1):1981202. doi: 10.1080/19420862.2021.1981202.
Bemarituzumab (FPA144) is a first-in-class, humanized, afucosylated immunoglobulin G1 monoclonal antibody (mAb) directed against fibroblast growth factor receptor 2b (FGFR2b) with two mechanisms of action against FGFR2b-overexpressing tumors: inhibition of FGFR2b signaling and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). Bemarituzumab is being developed as a cancer therapeutic, and we summarize here the key nonclinical data that supported moving it into clinical trials. Bemarituzumab displayed sub-nanomolar cross-species affinity for FGFR2b receptors, with >20-fold enhanced binding affinity to human Fc gamma receptor IIIa compared with the fucosylated version. In vitro, bemarituzumab induced potent ADCC against FGFR2b-expressing tumor cells, and inhibited FGFR2 phosphorylation and proliferation of SNU-16 gastric cancer cells in a concentration-dependent manner. In vivo, bemarituzumab inhibited tumor growth through inhibition of the FGFR2b pathway and/or ADCC in mouse models. Bemarituzumab demonstrated enhanced anti-tumor activity in combination with chemotherapy, and due to bemarituzumab-induced natural killer cell-dependent increase in programmed death-ligand 1, also resulted in enhanced anti-tumor activity when combined with an anti-programmed death-1 antibody. Repeat-dose toxicity studies established the highest non-severely-toxic dose at 1 and 100 mg/kg in rats and cynomolgus monkeys, respectively. In pharmacokinetic (PK) studies, bemarituzumab exposure increase was greater than dose-proportional, with the linear clearance in the expected dose range for a mAb. The PK data in cynomolgus monkeys were used to project bemarituzumab linear PK in humans, which were consistent with the observed human Phase 1 data. These key nonclinical studies facilitated the successful advancement of bemarituzumab into the clinic.

31Bemarituzumab as first-line treatment for locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma: final analysis of the randomized phase 2 FIGHT trial.PubMed

Zev A Wainberg, Yoon-Koo Kang, Keun-Wook Lee, et al.
Gastric Cancer. 2024 May;27(3):558-570. doi: 10.1007/s10120-024-01466-w. Epub 2024 Feb 3.
BACKGROUND: We report the final results of the randomized phase 2 FIGHT trial that evaluated bemarituzumab, a humanized monoclonal antibody selective for fibroblast growth factor receptor 2b (FGFR2b), plus mFOLFOX6 in patients with FGFR2b-positive (2 + /3 + membranous staining by immunohistochemistry), HER-2-negative gastric or gastroesophageal junction cancer (GC). METHODS: Patients received bemarituzumab (15 mg/kg) or placebo once every 2 weeks with an additional bemarituzumab (7.5 mg/kg) or placebo dose on cycle 1 day 8. All patients received mFOLFOX6. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, and safety. Efficacy was evaluated after a minimum follow-up of 24 months. RESULTS: In the bemarituzumab-mFOLFOX6 (N = 77) and placebo-mFOLFOX6 (N = 78) arms, respectively, 59.7% and 66.7% of patients were FGFR2b-positive in ≥ 10% of tumor cells. The median PFS (95% confidence interval [CI]) was 9.5 months (7.3-13.7) with bemarituzumab-mFOLFOX6 and 7.4 months (5.7-8.4) with placebo-mFOLFOX6 (hazard ratio [HR], 0.72; 95% CI 0.49-1.08); median OS (95% CI) was 19.2 (13.6-24.2) and 13.5 (9.3-15.9) months, respectively (HR 0.77; 95% CI 0.52-1.14). Observed efficacy in FGFR2b-positive GC in ≥ 10% of tumor cells was: PFS: HR 0.43 (95% CI 0.26-0.73); OS: HR 0.52 (95% CI 0.31-0.85). No new safety findings were reported. CONCLUSIONS: In FGFR2b-positive advanced GC, the combination of bemarituzumab-mFOLFOX6 led to numerically longer median PFS and OS compared with mFOLFOX6 alone. Efficacy was more pronounced with FGFR2b overexpression in ≥ 10% of tumor cells. Confirmatory phase 3 trials are ongoing (NCT05052801, NCT05111626). CLINICAL TRIAL REGISTRATION: NCT03694522.

32Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double-blind, placebo-controlled, phase 2 study.PubMed

Zev A Wainberg, Peter C Enzinger, Yoon-Koo Kang, et al.
Lancet Oncol. 2022 Nov;23(11):1430-1440. doi: 10.1016/S1470-2045(22)00603-9. Epub 2022 Oct 14.
BACKGROUND: Outcomes are poor in patients with HER2-negative, advanced gastric or gastro-oesophageal junction adenocarcinomas. In this study, we investigated efficacy and safety of the first-in-class, afucosylated, humanised IgG1 anti-fibroblast growth factor receptor 2 isoform IIb (FGFR2b) monoclonal antibody bemarituzumab with modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma. METHODS: In the randomised, double-blind, placebo-controlled phase 2 trial (FIGHT), patients aged 18 years and older with HER2 non-positive, FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma, and an Eastern Cooperative Oncology Group performance status of 0-1 were recruited from 144 clinical sites across 17 countries. Patients with previous treatment with any selective inhibitor of the FGF-FGFR pathway were excluded. Eligible patients were randomly assigned (1:1), using permuted-block randomisation (block size of four) and a central interactive voice-web-based response system, stratified by geographical region, previous treatment with curative intent, and administration of mFOLFOX6 while being screened for FGFR2b status, to either bemarituzumab (15 mg/kg of bodyweight) or matched placebo intravenously every 2 weeks. All patients also received mFOLFOX6 (oxaliplatin 85 mg/m, leucovorin 400 mg/m, and 5-fluorouracil as a 400 mg/m bolus followed by 2400 mg/m over approximately 46 h) intravenously every 2 weeks. Patients were given treatment until disease progression (defined by Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1), unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was progression-free survival in the intention-to-treat population (defined as all patients randomly assigned to treatment). Safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, NCT03694522, and is now complete. FINDINGS: Between Nov 14, 2017, and May 8, 2020, 910 patients were screened and 155 were randomly assigned to the bemarituzumab (n=77) or placebo group (n=78). Median age was 60·0 years (IQR 51·0-67·0), 44 (28%) participants were women, 111 (72%) were men, 89 (57%) were Asian, and 61 (39%) were White. At the time of the primary analysis and at a median follow-up of 10·9 months (IQR 6·3-14·2), median progression-free survival was 9·5 months (95% CI 7·3-12·9) in the bemarituzumab group and 7·4 months (5·8-8·4) in the placebo group (hazard ratio [HR] 0·68 [95% CI 0·44-1·04; p=0·073). Common grade 3 or worse adverse events were decreased neutrophil count (23 [30%] of 76 in the bemarituzumab group vs 27 [35%] of 77 in the placebo group), cornea disorder (18 [24%] vs none), neutropenia (ten [13%] vs seven [9%]), stomatitis (seven [9%] vs one [1%]), and anaemia (six [8%] vs ten [13%]). Serious treatment-emergent adverse events were reported in 24 (32%) patients in the bemarituzumab group and 28 (36%) in the placebo group. Serious mFOLFOX6 treatment-related adverse events occurred in nine (12%) patients in the bemarituzumab group and in 15 (19%) patients in the placebo group. All-grade corneal events (adverse events of special interest) occurred in 51 (67%) patients in the bemarituzumab group and eight (10%) in the placebo group; grade 3 corneal events were reported only in 18 (24%) patients in the bemarituzumab group. Treatment-related deaths occurred in three patients in the bemarituzumab group (two due to sepsis, one due to pneumonia) and none in the placebo group. INTERPRETATION: In this exploratory phase 2 study, despite no statistically significant improvement in progression-free survival, treatment with bemarituzumab showed promising clinical efficacy. Confirmatory phase 3 trials of bemarituzumab plus mFOLFOX6 powered to demonstrate statistical significance are being investigated in patients with previously untreated, FGFR2b-overexpressing, advanced gastric or gastro-oesophageal junction adenocarcinoma. FUNDING: Five Prime Therapeutics.

33FGFR Inhibitor Stymies Gastric Cancer.PubMed

Cancer Discov. 2021 May;11(5):OF3. doi: 10.1158/2159-8290.CD-NB2021-0312. Epub 2021 Feb 11.
In the phase II FIGHT trial, adding bemarituzumab to chemotherapy led to longer progression-free survival and overall survival in patients with advanced FGFR2b-positive gastric or gastroesophageal junction cancers. However, the agent was also associated with more side effects, including eye problems.

34Bemarituzumab with modified FOLFOX6 for advanced FGFR2-positive gastroesophageal cancer: FIGHT Phase III study design.PubMed

Daniel Vt Catenacci, Anteneh Tesfaye, Mohamed Tejani, et al.
Future Oncol. 2019 Jun;15(18):2073-2082. doi: 10.2217/fon-2019-0141. Epub 2019 May 16.
Bemarituzumab is an afucosylated monoclonal antibody against FGFR2b (a FGF receptor) with demonstrated monotherapy clinical activity in patients with late-line gastric cancer whose tumors overexpress FGFR2b (NCT02318329). We describe the rationale and design of the FIGHT trial (NCT03343301), a global, randomized, double-blind, placebo-controlled Phase III study evaluating the role of bemarituzumab in patients with previously untreated, FGFR2b-overexpressing advanced gastroesophageal cancer. Patients are randomized in a blinded fashion to the combination of mFOLFOX6 and bemarituzumab or mFOLFOX6 and placebo. Eligible patients are selected based on the presence of either FGFR2b protein overexpression determined by immunohistochemistry or gene amplification determined by circulating tumor DNA. The primary end point is overall survival, and secondary end points include progression-free survival, objective response rate and safety.

35Multiple receptor tyrosine kinase activation attenuates therapeutic efficacy of the fibroblast growth factor receptor 2 inhibitor AZD4547 in FGFR2 amplified gastric cancer.PubMed

Jinjia Chang, Shanshan Wang, Zhe Zhang, et al.
Oncotarget. 2015 Feb 10;6(4):2009-22. doi: 10.18632/oncotarget.2987.
Fibroblast growth factor receptor 2 (FGFR2)-targeted therapy has attracted considerable attention as novel anticancer agents in gastric cancer (GC). However, intrinsic or acquired drug resistance has emerged as a major challenge to their clinical use. In this study, we demonstrated that several receptor tyrosine kinase (RTK), including EGFR, HER3 and MET, activations contributed to AZD4547 (a selective FGFR2 inhibitor) hyposensitivity in FGFR2 amplified GC cells. The rescue effect was abrogated by inhibiting these RTKs with their targeted tyrosine kinase inhibitors (TKIs). In addition, synergy in growth inhibition was observed when the GC cells were treated with a combination of AZD4547 and cetuximab (an EGFR monoclonal antibody) both in vitro and in vivo. More importantly, tissue microarray analysis revealed that these resistance-conferring RTKs were highly expressed in FGFR2 positive GC patients. Taken together, these observations demonstrated RTKs including EGFR, HER3 and MET activations as novel mechanisms of hyposensitivity to AZD4547. It will be clinically valuable to investigate the involvement of RTK-mediated signaling in intrinsicor acquired resistance to FGFR2 TKIs in GC. A combination targeted therapeutic strategy may be recommended for treating FGFR2 amplified GC patients with these RTK activations.

36Phase 2 study of futibatinib in patients with gastric or gastroesophageal junction cancer harboring FGFR2 amplifications.PubMed

Taroh Satoh, Philippe Barthélémy, Lucia Nogova, et al.
Eur J Cancer. 2025 Mar 11;218:115262. doi: 10.1016/j.ejca.2025.115262. Epub 2025 Jan 27.
BACKGROUND AND AIMS: Aberrant fibroblast growth factor receptor (FGFR)-driven signaling, predominantly arising from FGFR2 amplification, plays a key role in gastric cancer pathogenesis. This open-label, phase 2 study evaluated the efficacy and safety of futibatinib, an irreversible FGFR1-4 inhibitor, in patients with gastric or gastroesophageal junction (GEJ) cancer harboring FGFR2 amplifications. METHODS: Patients were treated with futibatinib 20 mg orally once daily in a 28-day cycle. The primary endpoint was objective response rate (ORR) per independent central review. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Among 28 treated patients, the ORR per independent central review was 17.9 %, comprising five patients with a partial response (median duration of response, 3.9 months), and an additional nine patients with stable disease for a disease control rate of 50.0 %. Median PFS per independent central review and median OS were 2.9 and 5.9 months, respectively. The most common treatment-related adverse events (any grade) were hyperphosphatemia (89.3 %), decreased appetite (32.1 %), and increased aspartate aminotransferase (21.4 %). Only one (3.6 %) patient discontinued study treatment due to an adverse event. Futibatinib demonstrated modest antitumor activity with a safety profile consistent with previous reports in patients with gastric or GEJ cancer harboring FGFR2 amplifications, potentially warranting further investigation.

37Tumour cell responses to new fibroblast growth factor receptor tyrosine kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of acquired resistance.PubMed

V Chell, K Balmanno, A S Little, et al.
Oncogene. 2013 Jun 20;32(25):3059-70. doi: 10.1038/onc.2012.319. Epub 2012 Aug 6.
Fibroblast growth factor receptors (FGFRs) can act as driving oncoproteins in certain cancers, making them attractive drug targets. Here we have characterized tumour cell responses to two new inhibitors of FGFR1-3, AZ12908010 and the clinical candidate AZD4547, making comparisons with the well-characterized FGFR inhibitor PD173074. In a panel of 16 human tumour cell lines, the anti-proliferative activity of AZ12908010 or AZD4547 was strongly linked to the presence of deregulated FGFR signalling, indicating that addiction to deregulated FGFRs provides a therapeutic opportunity for selective intervention. Acquired resistance to targeted tyrosine kinase inhibitors is a growing problem in the clinic but has not yet been explored for FGFR inhibitors. To assess how FGFR-dependent tumour cells adapt to long-term FGFR inhibition, we generated a derivative of the KMS-11 myeloma cell line (FGFR(Y373C)) with acquired resistance to AZ12908010 (KMS-11R cells). Basal phosphorylated FGFR and FGFR-dependent downstream signalling were constitutively elevated and refractory to drug in KMS-11R cells. Sequencing of FGFR3 in KMS-11R cells revealed the presence of a heterozygous mutation at the gatekeeper residue, encoding FGFR3(V555M); consistent with this, KMS-11R cells were cross-resistant to AZD4547 and PD173074. These results define the selectivity and efficacy of two new FGFR inhibitors and identify a secondary gatekeeper mutation as a mechanism of acquired resistance to FGFR inhibitors that should be anticipated as clinical evaluation proceeds.

38Dysregulated lipids homeostasis disrupts CHAC1-mediated ferroptosis driving fibroblast growth factor receptor tyrosine kinase inhibitor AZD4547 resistance in gastric cancer.PubMed

Jingwen Chen, Yedi Huang, Daocheng Zuo, et al.
Redox Biol. 2025 Jul;84:103693. doi: 10.1016/j.redox.2025.103693. Epub 2025 May 22.
AIMS: This study investigates the mechanisms underlying acquired resistance to FGFR tyrosine kinase inhibitor (FGFR-TKI) in gastric cancer (GC), focusing on the interplay between ferroptosis and lipid metabolism of tumor cells. METHODS: We constructed FGFR-TKI-resistant cell lines from GC cells. RNA sequencing was performed to identify differentially expressed genes (DEGs) related to ferroptosis and assess lipid metabolism in resistant cells. GC microenvironment lipid profile was characterized by HPLC-MS/MS lipidomics. The effects of CHAC1 and cholesterol synthesis modulation on ferroptosis and FGFR-TKI resistance were assessed using in vitro and in vivo models. RESULTS: We found that FGFR-TKI can induce ferroptosis in FGFR-TKI-sensitive cells, while resistant cells exhibit decreased sensitivity to ferroptosis due to reduced CHAC1 expression, a key glutathione-specific degrading enzyme. Overexpression of CHAC1 enhances FGFR-TKI cytotoxicity. Additionally, cholesterol accumulation in resistant cells, associated with diminished stearic acid (SA) uptake, confers FGFR-TKI-induced ferroptosis resistance. In vivo studies show that CHAC1 overexpression or cholesterol synthesis inhibition can reverse FGFR-TKI resistance, which is dependent on ferroptosis. CONCLUSIONS: Dysregulated lipid homeostasis downregulated CHAC1-mediated ferroptosis, leading to FGFR-TKI resistance in gastric cancer. Overexpression of CHAC1 or inhibiting cholesterol synthesis presents promising therapeutic strategies to overcome FGFR-TKI resistance in GC.

39Nivolumab Combined with Chemotherapy in FGFR2 and PD-L1 Co-Expressing Metastatic Gastric Cancer: A Prospective Phase 2 NIVOFGFR2 Study.PubMed

Ilya Tsimafeyeu, Gunel Musayeva, Samira Mahmudova, et al.
J Gastrointest Cancer. 2025 Jan 11;56(1):40. doi: 10.1007/s12029-025-01172-5.
BACKGROUND: Immunotherapy is increasingly significant in treating metastatic gastric cancer. This prospective phase 2 study investigates the efficacy and safety of combining nivolumab with chemotherapy in patients with metastatic gastric cancer co-expressing FGFR2 and PD-L1. METHODS: Eligible patients were aged 18 years or older, with previously untreated HER-2 negative, PD-L1 positive, and FGFR2 positive metastatic gastric adenocarcinoma. Patients received nivolumab (360 mg every 3 weeks) in combination with chemotherapy (CAPOX: capecitabine 1000 mg/m twice daily on days 1-14 and oxaliplatin 130 mg/m on day 1, every 3 weeks). Tumor assessments were conducted using RECIST v1.1 every 8 weeks for 48 weeks, then every 12 weeks. The primary endpoint was the 1-year progression-free survival (PFS) rate. Secondary endpoints included median PFS, overall survival (OS), objective response rate (ORR), and grade ≥ 3 adverse events (AEs). RESULTS: From June 2022 to October 2023, 194 patients were assessed for eligibility, with 23 patients enrolled and treated. At a median follow-up of 17.3 months, the 1-year PFS rate was 30.4%, with a median PFS of 6.0 months (95% CI, 4.3-7.7). The median OS was 15.1 months (95% CI, 13.2-16.8). The ORR was 21.7%, with one complete response and four partial responses. Grade 3 or higher TRAEs were reported in 34.8% of patients, primarily associated with chemotherapy. No treatment-related deaths occurred. CONCLUSIONS: While the primary endpoint of improved 1-year PFS rate was not met, the study offers valuable insights into the potential benefits of combining nivolumab with chemotherapy in FGFR2 and PD-L1 co-expressing metastatic gastric cancer. Future research should optimize patient selection, assess combined immunotherapy and targeted anti-FGFR2 therapy, and further investigate the role of subsequent treatments to maximize therapeutic benefits.

40New developments and standard of care in the management of advanced gastric cancer.PubMed

Léonard Depotte, Juliette Palle, Cosimo Rasola, et al.
Clin Res Hepatol Gastroenterol. 2024 Jan;48(1):102245. doi: 10.1016/j.clinre.2023.102245. Epub 2023 Nov 11.
Advanced gastric adenocarcinoma is a common disease with a poor prognosis whose treatment has for decades been based on cytotoxic chemotherapy, including platinum salts in first-line, and taxane or irinotecan in second or later line. Recent years have seen the emergence of new drugs that have improved patient survival, such as trastuzumab in first-line for HER2-positive tumors, ramucirumab alone or in combination with paclitaxel in second-line, and trifluridine-tipiracil beyond the second-line treatment. More recently, two monoclonal antibodies have demonstrated their efficacy in combination with oxaliplatin-based first-line chemotherapy, nivolumab (anti-PD1) for PD-L1 CPS ≥5 tumors, and zolbetuximab for tumors overexpressing Claudin 18.2. In addition, regorafenib has been also showed effective in phase 3 trial for heavily pretreated patients. Based on phase 2 studies, trastuzumab-deruxtecan was approved in 2022 by the EMA for HER2-positive pretreated patients. This agent is currently evaluated in phase 3 study (DESTINY-Gastric04 trial), as are several other anti-HER2 (zanidatamab, margetuximab, tucatinib), immune checkpoint inhibitors, or targeted therapies (anti-FGFR2b).

41The Irreversible FGFR Inhibitor KIN-3248 Overcomes FGFR2 Kinase Domain Mutations.PubMed

Eranga R Balasooriya, Qibiao Wu, Haley Ellis, et al.
Clin Cancer Res. 2024 May 15;30(10):2181-2192. doi: 10.1158/1078-0432.CCR-23-3588.
PURPOSE: FGFR2 and FGFR3 show oncogenic activation in many cancer types, often through chromosomal fusion or extracellular domain mutation. FGFR2 and FGFR3 alterations are most prevalent in intrahepatic cholangiocarcinoma (ICC) and bladder cancers, respectively, and multiple selective reversible and covalent pan-FGFR tyrosine kinase inhibitors (TKI) have been approved in these contexts. However, resistance, often due to acquired secondary mutations in the FGFR2/3 kinase domain, limits efficacy. Resistance is typically polyclonal, involving a spectrum of different mutations that most frequently affect the molecular brake and gatekeeper residues (N550 and V565 in FGFR2). EXPERIMENTAL DESIGN: Here, we characterize the activity of the next-generation covalent FGFR inhibitor, KIN-3248, in preclinical models of FGFR2 fusion+ ICC harboring a series of secondary kinase domain mutations, in vitro and in vivo. We also test select FGFR3 alleles in bladder cancer models. RESULTS: KIN-3248 exhibits potent selectivity for FGFR1-3 and retains activity against various FGFR2 kinase domain mutations, in addition to being effective against FGFR3 V555M and N540K mutations. Notably, KIN-3248 activity extends to the FGFR2 V565F gatekeeper mutation, which causes profound resistance to currently approved FGFR inhibitors. Combination treatment with EGFR or MEK inhibitors potentiates KIN-3248 efficacy in vivo, including in models harboring FGFR2 kinase domain mutations. CONCLUSIONS: Thus, KIN-3248 is a novel FGFR1-4 inhibitor whose distinct activity profile against FGFR kinase domain mutations highlights its potential for the treatment of ICC and other FGFR-driven cancers.

42Tumor heterogeneity and acquired drug resistance in FGFR2-fusion-positive cholangiocarcinoma through rapid research autopsy.PubMed

Melanie A Krook, Russell Bonneville, Hui-Zi Chen, et al.
Cold Spring Harb Mol Case Stud. 2019 Aug 1;5(4). doi: 10.1101/mcs.a004002. Print 2019 Aug.
Cholangiocarcinoma is a highly aggressive and lethal malignancy, with limited treatment options available. Recently, FGFR inhibitors have been developed and utilized in FGFR-mutant cholangiocarcinoma; however, resistance often develops and the genomic determinants of resistance are not fully characterized. We completed whole-exome sequencing (WES) of 11 unique tumor samples obtained from a rapid research autopsy on a patient with FGFR-fusion-positive cholangiocarcinoma who initially responded to the pan-FGFR inhibitor, INCB054828. In vitro studies were carried out to characterize the novel FGFR alteration and secondary mutation identified. Multisite WES and analysis of tumor heterogeneity through subclonal inference identified four genetically distinct cancer cell populations, two of which were only observed after treatment. Additionally, WES revealed an N549H mutation hypothesized to confer resistance to the FGFR inhibitor INCB054828 in a single tumor sample. This hypothesis was corroborated with in vitro cell-based studies in which cells expressing fusion were sensitive to INCB054828 (IC value of 10.16 nM), whereas cells with the addition of the N549H mutation were resistant to INCB054828 (IC value of 1527.57 nM). Furthermore, the N549H secondary mutation displayed cross-resistance to other selective FGFR inhibitors, but remained sensitive to the nonselective inhibitor, ponatinib. Rapid research autopsy has the potential to provide unprecedented insights into the clonal evolution of cancer throughout the course of the disease. In this study, we demonstrate the emergence of a drug resistance mutation and characterize the evolution of tumor subclones within a cholangiocarcinoma disease course.

43Upregulation of EphB3 in gastric cancer with acquired resistance to a FGFR inhibitor.PubMed

Suk-Young Lee, Yoo Jin Na, Yoon A Jeong, et al.
Int J Biochem Cell Biol. 2018 Sep;102:128-137. doi: 10.1016/j.biocel.2018.07.008. Epub 2018 Jul 22.
Amplification of fibroblast growth factor receptor2 (FGFR2) has been regarded as a druggable target in gastric cancer (GC). Despite known potential of AZD4547, a selective inhibitor of FGFR 1-3, to suppress tumorigenic effects of activated FGFR2, resistance to the targeted agent has been an unresolved issue. This study was performed to elucidate the mechanism of AZD4547 resistance in GC cells. SNU-16 cells were used to establish an AZD4547-resistant GC cell line, SNU-16R. Elevated phosphorylation of EphB3 was confirmed using the Human Phospho-Receptor Tyrosine Kinase Array kit. A tyrosine kinase inhibitor (TKI) of EphB3 was used to investigate the effects of suppressed EphB3 activity in the SNU-16R cell line. SNU-16R cells exhibited upregulated phosphorylation of EphB3. Treatment of SNU-16R cells with the EphB3 TKI resulted in induction of apoptosis, decreased cellular viability, and cell cycle arrest at sub-G1 phase. SNU-16R cells expressed upregulated levels of N-cadherin, vimentin, Snail, matrix metalloproteinase 2 (MMP-2), and MMP-9, and reduced levels of E-cadherin, characteristic of epithelial to mesenchymal transition (EMT). Matrigel invasion assay also demonstrated the increased invasiveness of SNU-16R cells. EphB3 TKI treatment inhibited EMT of SNU-16R cells. Activation of mammalian target of rapamycin (mTOR) through the Ras-ERK1/2 pathway was suggested as the signal transduction mechanism downstream EphB3 by showing enhanced phosphorylation of Raf-1, MEK1/2, ERK1/2, mTOR and its downstream substrates in SNU-16R cells. As expected, EphB3 TKI decreased phosphorylation of these proteins. Our data suggest phosphorylation of mTOR through signaling by EphB3 is a potential mechanism of AZD4547 resistance in GC cells.

44Rescue screens with secreted proteins reveal compensatory potential of receptor tyrosine kinases in driving cancer growth.PubMed

Fred Harbinski, Vanessa J Craig, Sneha Sanghavi, et al.
Cancer Discov. 2012 Oct;2(10):948-59. doi: 10.1158/2159-8290.CD-12-0237. Epub 2012 Aug 8.
The overall power of kinase inhibitors is substantially overshadowed by the acquisition of drug resistance. To address this issue, we systematically assessed the potential of secreted proteins to induce resistance to kinase inhibitors. To this end, we developed a high-throughput platform for screening a cDNA library encoding 3,432 secreted proteins in cellular assays. Using cancer cells originally dependent on either MET, FGFR2, or FGFR3, we observed a bypass of dependence through ligand-mediated activation of alternative receptor tyrosine kinases (RTK). Our findings indicate a broad and versatile potential for RTKs from the HER and FGFR families as well as MET to compensate for loss of each other. We further provide evidence that combined inhibition of simultaneously active RTKs can lead to an added anticancer effect.

45Acquired resistance to LY2874455 in FGFR2-amplified gastric cancer through an emergence of novel FGFR2-ACSL5 fusion.PubMed

Sun Young Kim, Taejin Ahn, Heejin Bang, et al.
Oncotarget. 2017 Feb 28;8(9):15014-15022. doi: 10.18632/oncotarget.14788.
BACKGROUND: Fibroblast growth factor 2 (FGFR2) amplification, occurring in ~2-9% of gastric cancers (GC), is associated with poor overall survival. RESULTS: RNA sequencing identified a novel FGFR2-ACSL5 fusion in the resistant tumor that was absent from the matched pre-treatment tumor. The FGFR2-amplified PDC line was sensitive to FGFR inhibitors whereas the PDC line with concomitant FGFR2 amplification and FGFR2-ACSL5 fusion exhibited resistance. Additionally, the FGFR2-amplified GC PDC line, which was initially sensitive to FGFR2 inhibitors, subsequently also developed resistance. MATERIALS AND METHODS: We identified an FGFR2-amplified patient with GC, who demonstrated a dramatic and long-term response to LY2874455, a pan-FGFR inhibitor, but eventually developed an acquired LY2874455 resistance. Following resistance development, an endoscopic biopsy was performed for transcriptome sequencing and patient-derived tumor cell line (PDC) establishment to elucidate the underlying molecular alterations. CONCLUSIONS: FGFR inhibitors may function against FGFR2-amplified GC, and a novel FGFR2-ACSL5 fusion identified by transcriptomic characterization may underlie clinically acquired resistance. IMPLICATIONS FOR PRACTICE: Poor treatment response represents a substantial concern in patients with gastric cancer carrying multiple FGFR2 gene copies. Here, we show the utility of a general FGFR inhibitor for initial response prior to treatment resistance and report the first characterization of a potential resistance mechanism involving an FGFR2-ACSL5 fusion protein.

46A Novel Receptor Tyrosine Kinase Switch Promotes Gastrointestinal Stromal Tumor Drug Resistance.PubMed

Sergei Boichuk, Aigul Galembikova, Pavel Dunaev, et al.
Molecules. 2017 Dec 5;22(12):2152. doi: 10.3390/molecules22122152.
The fact that most gastrointestinal stromal tumors (GISTs) acquire resistance to imatinib (IM)-based targeted therapy remains the main driving force to identify novel molecular targets that are capable to increase GISTs sensitivity to the current therapeutic regimens. Secondary resistance to IM in GISTs typically occurs due to several mechanisms that include hemi- or homo-zygous deletion of the wild-type KIT allele, overexpression of focal adhesion kinase (FAK) and insulin-like growth factor receptor I (IGF-1R) amplification, BRAF mutation, a RTK switch (loss of c-KIT and gain of c-MET/AXL), etc. We established and characterized the IM-resistant GIST T-1 cell line (GIST T-1R) lacking secondary c-KIT mutations typical for the IM-resistant phenotype. The resistance to IM in GIST T-1R cells was due to RTK switch (loss of c-KIT/gain of FGFR2α). Indeed, we have found that FGFR inhibition reduced cellular viability, induced apoptosis and affected the growth kinetics of the IM-resistant GISTs in vitro. In contrast, IM-naive GIST T-1 parental cells were not susceptible to FGFR inhibition. Importantly, inhibition of FGF-signaling restored the susceptibility to IM in IM-resistant GISTs. Additionally, IM-resistant GISTs were less susceptible to certain chemotherapeutic agents as compared to parental IM-sensitive GIST cells. The chemoresistance in GIST T-1R cells is not due to overexpression of ABC-related transporter proteins and might be the result of upregulation of DNA damage signaling and repair (DDR) genes involved in DNA double-strand break (DSB) repair pathways (e.g., XRCC3, Rad51, etc.). Taken together, the established GIST T-1R cell subline might be used for in vitro and in vivo studies to examine the efficacy and prospective use of FGFR inhibitors for patients with IM-resistant, un-resectable and metastatic forms of GISTs with the type of RTK switch indicated above.

47Acquired JHDM1D-BRAF Fusion Confers Resistance to FGFR Inhibition in -Amplified Gastric Cancer.PubMed

Hitoshi Sase, Yoshito Nakanishi, Satoshi Aida, et al.
Mol Cancer Ther. 2018 Oct;17(10):2217-2225. doi: 10.1158/1535-7163.MCT-17-1022. Epub 2018 Jul 25.
gene is frequently amplified in gastric cancer. Recently, targeting FGFR2 has drawn attention as a form of gastric cancer therapy, and FGFR-selective inhibitors have shown promising efficacy in clinical studies. Because overcoming acquired resistance is a common problem with molecular targeting drugs, we investigated a resistant mechanism of FGFR inhibitors using the gastric cancer cell line SNU-16, which harbors amplification. We established single-cell clones of FGFR inhibitor-resistant SNU-16 (AZD-R) by continuous exposure to AZD4547, a selective FGFR inhibitor. To screen the genetic alterations acquired in AZD-R, we ran a comparative genomic hybridization assay and found an amplification of Chr7q34 region. The chromosomal breakpoints were located between the 12th and the 13th exon of jumonji C domain containing histone demethylase 1 homolog D () and between the 3rd and the 4th exon of We sequenced cDNA of the AZD-R clones and found fusion kinase , which has previously been identified in primary ovarian cancer. Because JHDM1D-BRAF fusion lacks a RAS-binding domain, the dimerization of JHDM1D-BRAF was enhanced. A cell growth inhibition assay using MEK inhibitors and RAF-dimer inhibitors indicated the dependence of AZD-R clones for growth on the MAPK pathway. Our data provide a clinical rationale for using a MEK or RAF dimer inhibitor to treat -amplified gastric cancer patients who have acquired resistance through the JHDN1D-BRAF fusion. .

48Enhancing transcription-replication conflict targets ecDNA-positive cancers.PubMed

Jun Tang, Natasha E Weiser, Guiping Wang, et al.
Nature. 2024 Nov;635(8037):210-218. doi: 10.1038/s41586-024-07802-5. Epub 2024 Nov 6.
Extrachromosomal DNA (ecDNA) presents a major challenge for cancer patients. ecDNA renders tumours treatment resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival. At present, there are no ecDNA-specific treatments. Here we show that enhancing transcription-replication conflict enables targeted elimination of ecDNA-containing cancers. Stepwise analyses of ecDNA transcription reveal pervasive RNA transcription and associated single-stranded DNA, leading to excessive transcription-replication conflicts and replication stress compared with chromosomal loci. Nucleotide incorporation on ecDNA is markedly slower, and replication stress is significantly higher in ecDNA-containing tumours regardless of cancer type or oncogene cargo. pRPA2-S33, a mediator of DNA damage repair that binds single-stranded DNA, shows elevated localization on ecDNA in a transcription-dependent manner, along with increased DNA double strand breaks, and activation of the S-phase checkpoint kinase, CHK1. Genetic or pharmacological CHK1 inhibition causes extensive and preferential tumour cell death in ecDNA-containing tumours. We advance a highly selective, potent and bioavailable oral CHK1 inhibitor, BBI-2779, that preferentially kills ecDNA-containing tumour cells. In a gastric cancer model containing FGFR2 amplified on ecDNA, BBI-2779 suppresses tumour growth and prevents ecDNA-mediated acquired resistance to the pan-FGFR inhibitor infigratinib, resulting in potent and sustained tumour regression in mice. Transcription-replication conflict emerges as a target for ecDNA-directed therapy, exploiting a synthetic lethality of excess to treat cancer.

49Synthesis and identification of a selective FGFR2 degrader with potent antiproliferative effects in gastric cancer.PubMed

Zhanzhan Feng, Shirui Wang, Su Yu, et al.
Eur J Med Chem. 2024 Nov 5;277:116780. doi: 10.1016/j.ejmech.2024.116780. Epub 2024 Aug 14.
Despite numerous efforts to develop FGFR inhibitors for cancer treatment, the widespread clinical application of currently available FGFR inhibitors has been significantly limited due to the serious side effects caused by poor selectivity and resistance. PROTAC technology, a method for protein degradation, has shown notable advantages over conventional inhibitors. In our study, we coupled Erdafitinib, a pan-FGFR inhibitor, with a CRBN binder to synthesize and identify an effective FGFR2 degrader, N5. Our findings demonstrated that N5 displayed notable specificity for FGFR2 and outstanding enzyme inhibitory capabilities, achieving an IC value of 0.08 nM against FGFR2, and strong antiproliferative activity, maintaining an inhibitory rate above 50% on gastric cancer cells at a concentration of 0.17 nM. Mechanistically, N5 induced gastric cancer cell cycle arrest at the G0/G1 phase and apoptosis by decreasing the levels of FGFR downstream proteins. Moreover, N5 demonstrated favorable pharmacokinetic characteristics with a bioavailability of 74.8% when administered intraperitoneally and effectively suppressed the growth of SNU16 xenograft tumors, exhibiting greater potency compared to the parental inhibitor Erdafitinib. This study lays the groundwork for developing and potentially applying therapeutic agents targeting FGFR2 degradation.

50Design, synthesis and antitumor activity of a novel FGFR2-selective degrader to overcome resistance of the FGFR2 gatekeeper mutation based on a pan-FGFR inhibitor.PubMed

Zuli Hu, Qiangsheng Zhang, Zulong Li, et al.
Eur J Med Chem. 2024 Sep 5;275:116612. doi: 10.1016/j.ejmech.2024.116612. Epub 2024 Jun 18.
Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to the development and progression of multiple types of cancer. Although many FGFR inhibitors have been approved by the FDA, their long-term therapeutic efficacy is hampered by acquired resistance to gatekeeper mutations and low subtype selectivity. FGFR2 has been found to be frequently amplified or mutated in many tumors. In this study, we designed several PROTACs with different E3 ligands based on LY2874455. By screening the length of the linker and the binding site in various degraders, we obtained a novel and highly efficient FGFR2-selective degrader 28e (DC = 0.645 nM, DC = 86 %). Compound 28e selectively degraded FGFR2 and essentially avoided degradation of FGFR1,3,4 isoforms (DC > 300 nM). Compound 28e significantly inhibited the proliferation of FGFR2-overexpressing cell lines, including KATOIII, SNU16, and AN3CA (IC = 0.794 nM/0.207 nM/4.626 nM), comparable to parental inhibitors. At the same time, the preferred compound showed superiority over the parental inhibitor in kinase inhibitory activity against the gatekeeper mutant isoform FGFR2 (IC = 0.121 nM). In summary, we identified 28e as a novel selective degrader of FGFR2 with high potency and high potential to overcome resistance to gatekeeper mutation. The discovery of 28e provides new evidence for the strategy of pan-inhibitor-based development of selective degrading agents.

51Precision Detection of FGFR2b Protein Expression in Solid Tumors.PubMed

Autumn Sky Watson, Catherine Le, Anne Wertheimer, et al.
Arch Pathol Lab Med. 2025 Nov 1;149(11):1016-1021. doi: 10.5858/arpa.2024-0497-OA.
CONTEXT.—: Immunohistochemistry effectively reveals the heterogeneous nature of fibroblast growth factor receptor 2b (FGFR2b) expression and antigen accessibility across diverse tumor histologic types, a variability significantly influenced by tissue type and fixation quality, both of which profoundly impact target antigen accessibility within formalin-fixed, paraffin-embedded (FFPE) tissue specimens. Retrieval parameters on automated staining platforms can impact staining outcomes and assay sensitivity. A comprehensive optimization of staining procedures, encompassing antigen retrieval, proteolytic enzyme digestion, primary antibody incubation, and detection selections, yielded 2 distinct protocols designed for specific tumor types. The protocols were tailored to maximize performance on their respective tumor types, with one protocol optimized for gastric and gastroesophageal junction (G/GEJ) adenocarcinoma, and the other fine-tuned for non-small cell lung cancer (NSCLC) and a broader spectrum of solid tumors. OBJECTIVE.—: To optimize an FGFR2b (FPR2-D) assay for NSCLC and a broader spectrum of solid tumors through modification of the established VENTANA FGFR2b (FPR2-D) Mouse Monoclonal Antibody assay, originally validated for G/GEJ adenocarcinoma. DESIGN.—: Multiple FGFR2b assay protocols were used to stain sections of FFPE tissue from commercially procured specimens spanning 10 tumor types. Each specimen was evaluated to select the preferred protocol parameters that achieved strong specific staining with minimal background. The assay was then assessed for sensitivity, specificity, and repeatability. RESULTS.—: The optimal gastric cancer tissue staining protocol for the VENTANA FGFR2b (FPR2-D) Mouse Monoclonal Antibody was referenced to develop an assay for other solid tumor types. CONCLUSIONS.—: This investigation shows the importance of parameter screening approaches when evaluating FGFR2b across tumor types in immunohistochemistry to ensure optimal staining performance.

52The Role of FGFR2 as a Novel Biomarker for Treatment of Gastric Cancer-A Literature Review.PubMed

João Lages Dos Santos, Rui Caetano Oliveira, João Martins Gama
Medicina (Kaunas). 2025 Oct 22;61(11):1890. doi: 10.3390/medicina61111890.
BACKGROUND: Gastric cancer currently has the third highest mortality rate worldwide among cancer types. Despite gradual declines in mortality rates attributed to improvements in early detection and treatment, outcomes for advanced-stage disease are still poor. The identification of new biomarkers such as fibroblast growth factor receptor 2 (FGFR2) has opened new pathways for directed therapy in gastric cancer. OBJECTIVE: This review aims to synthesize the current evidence on the role of FGFR2 in gastric cancer, focusing on its biological function and oncogenic mechanisms, diagnostic and prognostic modification, therapeutic targeting, and possible roadblocks in clinical application. METHODS: A comprehensive literature search was conducted, selecting studies published between 2015 and 2025 using the MeSH terms "FGFR2 protein, human" [Supplementary Concept]) AND "Stomach Neoplasms". Articles were screened based on relevance to gastric cancer, language (English), and availability of full text, yielding a final selection of 75 studies, including preclinical research, clinical trials, and reviews. FINDINGS: We compiled and reported the evidence on FGFR2 detection methods, intra-tumoral heterogeneity of FGFR2 expression, effects of FGFR2 expression on prognosis, current therapy options targeting FGFR2, and challenges in pursuing this modality of treatment. CONCLUSION: FGFR2 represents a promising biomarker and therapeutic target in gastric cancer.

53Novel Biomarkers of Gastric Cancer: Current Research and Future Perspectives.PubMed

Yasushi Sato, Koichi Okamoto, Yutaka Kawano, et al.
J Clin Med. 2023 Jul 12;12(14):4646. doi: 10.3390/jcm12144646.
Gastric cancer is a heterogeneous disease with diverse histological and genomic subtypes, making it difficult to demonstrate treatment efficacy in clinical trials. However, recent efforts have been made to identify molecular biomarkers with prognostic and predictive implications to better understand the broad heterogeneity of gastric cancer and develop effective targeted therapies for it. HER2 overexpression, HER2/neu amplification, MSI-H, and PD-L1+ are predictive biomarkers in gastric cancer, and a growing number of clinical trials based on novel biomarkers have demonstrated the efficacy of targeted therapies alone or in combination with conventional chemotherapy. Enrichment design clinical trials of targeted therapies against FGFR2b and claudin 18.2 have demonstrated efficacy in unresectable advanced gastric cancer. Nonetheless, it is essential to continuously validate promising molecular biomarkers and introduce them into clinical practice to optimize treatment selection and improve patient outcomes. In this review, we focused on established (PD-L1, HER2, MSI) and emerging biomarkers (FGFR2, CLDN18.2) in gastric cancer, their clinical significance, detection methods, limitations, and molecular agents that target these biomarkers.

54Precision Antibody Therapy in Gastric and Gastroesophageal Cancer: Targeting FGFR2b, CLDN18.2, and VEGFR2.PubMed

Vivian Chetachi Eziefula Njoku, Yein Lee, Joytish Ramesh, et al.
Cells. 2025 Oct 26;14(21):1672. doi: 10.3390/cells14211672.
Gastric and gastroesophageal junction (G/GEJ) adenocarcinomas remain among the most aggressive and lethal malignancies globally. Most patients are diagnosed at advanced stages and respond poorly to conventional chemotherapy, highlighting the urgent demand for more effective, novel treatment strategies such as monoclonal antibody therapies targeting drivers of tumor progression. This review examines the mechanisms, safety profiles, and clinical trial outcomes of three targeted agents-bemarituzumab, zolbetuximab, and ramucirumab-which inhibit tumor growth through the FGFR2b, CLDN18.2, and VEGFR2 pathways, respectively. We also compare traditional versus adaptive clinical trial designs, explore emerging challenges such as therapeutic resistance and treatment-related toxicities, and consider implications for personalized medicine. Collectively, these agents represent a paradigm shift from empiric chemotherapy toward biomarker-driven immunotherapy, with the potential to significantly improve survival and quality of life in patients with advanced G/GEJ cancers.

55Targeted and combination immunotherapies using biologics for gastric cancer: the state-of-the-art.PubMed

Jane E Rogers, Qiong Gan, Rebecca E Waters, et al.
Expert Opin Biol Ther. 2024 Oct;24(10):1005-1015. doi: 10.1080/14712598.2024.2401622. Epub 2024 Oct 4.
INTRODUCTION: Gastric adenocarcinoma (GAC) remains a prevalent cancer worldwide and its incidence is increasing in South America. The heterogenous nature of GAC makes advances in management challenging. AREAS COVERED: Despite challenges, recent therapeutic targets are individualizing treatment. For localized disease with microsatellite-instability-high/deficient mismatch repair, immunotherapy is now an adopted practice. In the advanced unresectable setting, those harboring human epidermal growth factor receptor-2 (HER2) expression continue to be a separate entity. EXPERT OPINION: Future targets are developing. Among these include claudin 18.2 (CLDN18.2), fibroblast growth factor receptor 2b (FGFR2b), and trophoblast cell surface antigen-2 (TROP-2). FDA approval of zolbetuximab's, an anti-CLDN 18.2 monoclonal antibody, is expected soon. Additionally, bemarituzumab, ananti-FGFR2b monoclonal antibody, has shown improvements in combination with chemotherapy in those with HER2 negative GAC with FGFR2 overexpression. This combination is now being investigated in a phase 3 trial. Lastly, TROP-2 has emerged as an exciting solid tumor target and study is expected in GAC. All three of these therapeutic targets have seen an abundance of drug development in recent years, and we anticipate newer targeted agents driving therapeutic decisions in GAC in the coming years.

56Spatial and Temporal Tumor Heterogeneity in Gastric Cancer: Discordance of Predictive Biomarkers.PubMed

Hye Seung Lee
J Gastric Cancer. 2025 Jan;25(1):192-209. doi: 10.5230/jgc.2025.25.e3.
Gastric cancer (GC) is a highly heterogeneous disease that varies in both histological presentation and genetic characteristics. Recent advances in the treatment of metastatic and unresectable GC have made several biomarker tests essential for patient management. Predictive biomarkers such as human epidermal growth factor receptor 2 (HER2), programmed death-ligand 1 (PD-L1), mismatch-repair (MMR) proteins, claudin 18.2, and fibroblast growth factor receptor 2b (FGFR2b) are commonly evaluated using immunohistochemistry. However, the expression levels of these biomarkers may vary across different tumor areas, and the accuracy of biomarker diagnosis can be affected by sample quantity, sample location, and collection method. Therefore, tumor heterogeneity presents substantial challenges for accurate biomarker-based diagnosis and prediction of therapeutic responses. Tumor heterogeneity can be categorized into spatial heterogeneity, which refers to variations within the primary tumor (intra-tumoral) or between primary and metastatic sites, and temporal heterogeneity, which encompasses changes over time. This review addresses the tumor heterogeneity in predictive biomarker expression in GC, focusing on HER2, PD-L1, MMR, the Epstein-Barr virus, claudin 18.2, and FGFR2b.

57Spatially Resolved Niche and Tumor Microenvironmental Alterations in Gastric Cancer Peritoneal Metastases.PubMed

Joseph J Zhao, Chin-Ann Johnny Ong, Supriya Srivastava, et al.
Gastroenterology. 2024 Dec;167(7):1384-1398.e4. doi: 10.1053/j.gastro.2024.08.007. Epub 2024 Aug 13.
BACKGROUND & AIMS: Peritoneal metastasis (PM) in gastric cancer (GC) is associated with poor prognosis and significant morbidity. We sought to understand the genomic, transcriptomic, and tumor microenvironment (TME) features that contribute to peritoneal organotropism in GC. METHODS: We conducted a comprehensive multi-omic analysis of 548 samples from 326 patients, including primary tumors, matched normal tissues; peritoneal metastases, and adjacent-normal peritoneal tissues. We used whole exome sequencing, whole transcriptome sequencing, and digital spatial profiling to investigate molecular alterations, gene expression patterns, and TME characteristics associated with PM. RESULTS: Our analysis identified specific genomic alterations in primary tumors, including mutations in ELF3, CDH1, and PIGR, and TME signatures, such as stromal infiltration and M2 macrophage enrichment, associated with increased risk of PM. We observed distinct transcriptional programs and immune compositions in GCPM compared with liver metastases, highlighting the importance of the TME in transcoelomic metastasis. We found differential expression of therapeutic targets between primary tumors and PM, with lower CLDN18.2 and FGFR2b expression in PM. We unravel the roles of the TME in niche reprogramming within the peritoneum, and provide evidence of pre-metastatic niche conditioning even in early GC without clinical PM. These findings were further validated using a humanized mouse model, which demonstrated niche remodeling in the peritoneum during transcoelomic metastasis. CONCLUSION: Our study provides a comprehensive molecular characterization of GCPM and unveils key biological principles underlying transcoelomic metastasis. The identified predictive markers, therapeutic targets, and TME alterations offer potential avenues for targeted interventions and improved patient outcomes.

58Genomic complexity in advanced gastric and esophageal adenocarcinomas: a case report of rare -- fusions.PubMed

Eric Mehlhaff, Dustin A Deming, Jeremy D Kratz, et al.
Front Oncol. 2025 Nov 20;15:1686070. doi: 10.3389/fonc.2025.1686070. eCollection 2025.
Fibroblast growth factor receptor 2 (FGFR2) alterations represent an emerging therapeutic target in gastroesophageal adenocarcinoma (GEA). Although FGFR2 amplifications and overexpression have been associated with poor prognosis and therapeutic resistance, the clinical significant FGFR2 fusions, which are exceedingly rare, is unknown. Herein we describe two cases of advanced gastroesophageal and gastric adenocarcinomas characterized by aggressive disease course, rapid progression despite standard first-line chemoimmunotherapy, and the presence of high-level FGFR2 amplification with concurrent WDR11-AS1-FGFR2 fusion detected by circulating tumor DNA (ctDNA) analysis. These cases highlight the genomic complexity and aggressive behavior of FGFR2-driven GEA, underscored by coexisting genetic alterations. The findings emphasize the importance of comprehensive genomic profiling, including both tissue and liquid. in order to capture intratumoral heterogeneity and evolving molecular events. Further investigation of FGFR2 fusion biology and combinatorial therapeutic strategies is warranted to address the clinical challenge of biomarker overlap and treatment resistance in GEA.

59Investigating FGFR2 gene as a blood-based epigenetic biomarker in gastric cancer.PubMed

Seyed Ahmad Aleyasin, Arash Moradi, Naeimeh Abolhasani, et al.
Mol Biol Rep. 2024 Feb 1;51(1):253. doi: 10.1007/s11033-023-09082-0.
BACKGROUND: Gastric adenocarcinoma is a prevalent form of cancer that often remains undetected in its early stages due to the lack of specific symptoms. This delayed diagnosis leads to poor clinical outcomes, underscoring the need for an effective and non-invasive method for early detection. Recent advances in cancer epigenetics have led to the identification of biomarkers that have the potential to revolutionize the early detection and monitoring of this disease. One such promising biomarker is the methylation of the FGFR2 promoter. This study aims to measure the methylation levels of a specific CpG site in the FGFR2 promoter gene in DNA extracted from blood leukocytes from patients with intestinal metaplasia, gastric cancer, and healthy control. MATERIAL AND METHODS: The CpG site of the FGFR2 gene promoter was identified in its control region. Methylation alteration of the selected FGFR2 CpG site was determined through the (methylation-sensitive restriction enzyme) MSRE-qPCR. Genomic DNA was extracted from one hundred twenty-five participants. RESULTS: The normal group had mean methylation levels of 93.23 ± 4.929%, while the IM group had a level of 69.85 ± 27.15%. In GC patients, the levels varied, with 25.96 ± 18.98% in the intestinal type and 28.30 ± 16.07% in the diffuse type. The methylation levels in the IM and GC patients were significantly lower than those in the normal control group. However, no significant difference was observed between the methylation status of the intestinal type of GC and the diffuse type. The Receiver operating characteristic (ROC) curve analysis showed that FGFR2 CpG methylation levels in GC patients compared to normal controls had a high sensitivity of 100% and specificity of 100%, with a cut-off of < 74.25%; when GC patients were compared to IM patients, the sensitivity was 85%, and the specificity was 80%, with a cut-off < 44.45%. CONCLUSIONS: The potential of the FGFR2 methylation status as a non-invasive biomarker lies in its ability to be detected in blood leukocytes, which makes it a promising tool for the early detection of intestinal metaplasia and gastric cancer. This could significantly improve the detection and management of these gastric conditions.

60Fibroblast growth factor receptor (FGFR) inhibitors: A review of a novel therapeutic class.PubMed

April Weaver, John B Bossaer
J Oncol Pharm Pract. 2021 Apr;27(3):702-710. doi: 10.1177/1078155220983425. Epub 2020 Dec 29.
Comprehensive genomic profiling has an emerging role in cancer therapeutics. As treatment options remain needed for advanced cancers, patients are relying increasingly more on tumor genomic alterations as possible targets for cancer treatment. Frequent tumor fibroblast growth factor receptor (FGFR) alterations are seen in many cancers, and include genetic amplifications, mutations, rearrangements and fusions. FGFR inhibitors target these receptor alterations and show promise as a drug class. Currently 2 medications are currently FDA approved: erdafitinib and pemigatinib. Through the FDA accelerated approval process, erdafitinib is indicated to treat metastatic urothelial carcinoma with FGFR2 and FGFR3 alterations, whereas pemigatinib is indicated to treat unresectable cholangiocarcinoma with FGFR2 alterations. Despite growing knowledge about such advanced cancers, treatment is usually palliative. With multiple FGFR inhibitors in the pipeline, further FDA approvals are possible, and it is likely their role in therapy will extend to other cancer types. This review outlines erdafitinib, pemigatinib, their role in cancer, as well as outlining the possible future use of other FGFR inhibitors in urothelial carcinoma, cholangiocarcinoma, and other malignancies.

61New therapeutic target molecules for gastric and gastroesophageal junction cancer.PubMed

Hisato Kawakami
Int J Clin Oncol. 2024 Sep;29(9):1228-1236. doi: 10.1007/s10147-024-02521-3. Epub 2024 Apr 17.
Molecularly targeted therapy for receptor tyrosine kinases (RTKs) has faced limitations in gastric and gastroesophageal junction (G/GEJ) cancer except for HER2-targeted agents, possibly due to inappropriate assay selection that has hindered identification of sensitive patients, in addition to coexisting genetic abnormalities as well as intratumoral heterogeneity. Immunohistochemistry of RTKs has, thus, proved largely unsuccessful for patient selection, and detection of RTK gene amplification as a true oncogenic driver is problematic given the small numbers of affected individuals. FGFR2 amplification is associated with poor prognosis in G/GEJ cancer, and immunohistochemistry of the FGFR2b protein isoform has proved effective for the detection of such FGFR2-dependent tumors. Phase III and Ib/III trials of the FGFR2-targeted antibody bemarituzumab for G/GEJ cancer overexpressing FGFR2b are ongoing based on the promising result in a phase II trial, especially in cases with an FGFR2b positivity of ≥ 10%. Challenges to EGFR- and MET-targeted therapies are being tackled with antibody-drug conjugates (ADCs) and bispecific antibodies. CLDN18.2 is expressed in some G/GEJ tumors but lacks oncogenic driver potential, and the CLDN18.2-targeted antibody zolbetuximab prolonged the survival of CLDN18.2-positive G/GEJ cancer patients in phase III trials. Antibody-drug conjugates and ADCs that target CLDN18.2 are also being pursued for treatment of such patients. Similarly, targeting of nondriver molecules such as DKK1, TROP2, and CEACAM5 is under investigation in early-stage clinical trials. This shift in focus from target molecules with driver potential to markers for precise drug delivery should increase the number of possible targets in G/GEJ cancer.

62Application of spatial omics in gastric cancer.PubMed

Erran Zhu, Qi Xie, Xinqi Huang, et al.
Pathol Res Pract. 2024 Oct;262:155503. doi: 10.1016/j.prp.2024.155503. Epub 2024 Jul 30.
Gastric cancer (GC), a globally prevalent and lethal malignancy, continues to be a key research focus. However, due to its considerable heterogeneity and complex pathogenesis, the treatment and diagnosis of gastric cancer still face significant challenges. With the rapid development of spatial omics technology, which provides insights into the spatial information within tumor tissues, it has emerged as a significant tool in gastric cancer research. This technology affords new insights into the pathology and molecular biology of gastric cancer for scientists. This review discusses recent advances in spatial omics technology for gastric cancer research, highlighting its applications in the tumor microenvironment (TME), tumor heterogeneity, tumor genesis and development mechanisms, and the identification of potential biomarkers and therapeutic targets. Moreover, this article highlights spatial omics' potential in precision medicine and summarizes existing challenges and future directions. It anticipates spatial omics' continuing impact on gastric cancer research, aiming to improve diagnostic and therapeutic approaches for patients. With this review, we aim to offer a comprehensive overview to scientists and clinicians in gastric cancer research, motivating further exploration and utilization of spatial omics technology. Our goal is to improve patient outcomes, including survival rates and quality of life.

63Gastric cancer: from biomarkers to functional precision medicine.PubMed

Philipp Albrecht, Ekin Karabati, Matthias P Ebert, et al.
Trends Mol Med. 2025 Dec;31(12):1089-1102. doi: 10.1016/j.molmed.2025.05.007. Epub 2025 Jun 23.
Gastric cancer (GC) remains a deadly disease because of late detection and limited treatment options at advanced stages. Treatment of patients with metastatic disease is based on chemotherapy, complemented by antibodies targeting HER2, VEGFR2, and more recently PD-1 or claudin 18.2. Further targets, such as FGFR2b, as well as novel drug classes including antibody-drug conjugates (ADCs) and bispecific antibodies, are promising developments in GC treatment. Despite the failure of several targeted agents, the landscape of GC therapy is evolving rapidly, facilitated by umbrella or platform precision medicine trials. The integration of next-generation sequencing and other omics techniques into molecular tumor boards, as well as functional drug testing on patient-derived models, might bring us closer to personalized oncology and ultimately improve patient survival.

64[What's new in gastric cancer?].PubMed

Michael Masetti, Sylvie Lorenzen
Dtsch Med Wochenschr. 2024 Aug;149(17):1015-1020. doi: 10.1055/a-2179-0830. Epub 2024 Aug 15.
In the locally advanced stage, multimodal therapies such as perioperative chemotherapy with FLOT or neoadjuvant radiochemotherapy are recommended. The integration of immunotherapy into these concepts could improve the prognosis. Phase II/III trials such as DANTE, KEYNOTE-585 and MATTERHORN show promising results in terms of pathological remissions but data on survival time extension for unselected patients are so far sobering. Immunotherapies and new targeted therapies offer hope in the palliative treatment of metastatic gastric cancer. Studies such as CheckMate-649 and KEYNOTE-859 show an improvement in survival and response rates. Currently, both pembrolizumab and nivolumab have been approved for the first-line treatment of tumors with positive PD-L1 expression. In HER2-positive tumors, the KEYNOTE-811 study showed that patients benefit from combination therapies with immune checkpoint inhibition and anti-HER2 therapies. The antibody-drug conjugate trastuzumab-deruxtecan is a promising second-line treatment option for HER2-positive tumors after treatment failure with trastuzumab.In addition, the bispecific antibody zanidatamab shows promising results in first-line treatment. New targeted therapies against CLDN18.2 and FGFR2b are showing promising results. The anti-claudin 18.2 (CLDN18.2) antibody zolbetuximab leads to improved survival compared to chemotherapy alone in patients with CLDN18.2 positive disease in first-line therapy, with approval expected in 2024.