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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

深度研究匿名用户发表于 2025年10月23日 11:396阅读
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1. FGFR2b在胃癌中的生物学特性与病理意义

1.1 FGFR2b分子结构与信号通路特征

成纤维细胞生长因子受体2b（FGFR2b）是成纤维细胞生长因子受体（FGFR）家族中的一个重要成员，属于受体酪氨酸激酶（RTK）超家族。FGFR家族共有四种主要受体（FGFR1-4），它们在细胞增殖、分化、迁移和存活等多种生理过程中发挥关键作用。FGFR2b是FGFR2基因通过选择性剪接产生的一种异构体，其特点在于胞外区域的IIIb结构域，这赋予了它对特定配体成纤维细胞生长因子（FGFs）的高度特异性结合能力 1。

FGFR2b的典型结构包括一个胞外配体结合域、一个跨膜区和一个胞内酪氨酸激酶域。胞外区域由三个免疫球蛋白（Ig）样结构域（Ig1、Ig2和Ig3）组成，其中Ig3结构域通过选择性剪接形成IIIb和IIIc两种亚型，决定了受体与配体的结合特异性。FGFR2b特异性结合来自上皮细胞的FGF配体，如FGF7（也称为角质细胞生长因子，KGF）和FGF10，而FGFR2c则主要结合来自间充质细胞的FGFs 123。

在正常胃黏膜上皮中，FGFR2b的信号传导对于维持细胞稳态和组织修复至关重要。当FGF配体结合到FGFR2b后，会诱导受体二聚化，进而激活胞内酪氨酸激酶域的自磷酸化 45。磷酸化的酪氨酸残基为多种衔接蛋白提供结合位点，从而激活下游的多种信号通路，包括：

  1. RAS-MAPK（丝裂原活化蛋白激酶）通路：这是FGFR2b信号转导中最核心的通路之一。FGFR2b激活后，Grb2等衔接蛋白被募集到受体，进而激活Ras，并随后激活Raf、MEK和ERK。ERK的活化最终导致细胞增殖、分化和存活相关基因的表达 6。
  2. PI3K-AKT（磷脂酰肌醇3-激酶/蛋白激酶B）通路：FGFR2b的活化也可以募集PI3K，使其磷酸化并激活AKT。AKT是细胞生长、代谢、凋亡抑制和蛋白质合成的关键调控因子 7。
  3. PLCγ（磷脂酶Cγ）通路：活化的FGFR2b能够磷酸化PLCγ，导致膜脂质水解产生第二信使IP3和DAG，进而引起细胞内钙离子释放和蛋白激酶C的激活，参与细胞迁移和黏附的调控。

在胃癌中，FGFR2b的异常激活常表现为基因扩增、点突变或过表达，导致上述信号通路的持续激活，从而促进肿瘤细胞的增殖、血管生成、侵袭和转移，并与不良预后相关 78。例如，FGFR2扩增在胃癌中已被确认为一个重要的驱动基因改变，部分胃癌细胞系如KATO-III和OCUM-2M即表现出FGFR2扩增并对FGFR抑制剂敏感 9。此外，研究表明，FGFR2b信号传导还可以通过上调血小板反应蛋白-1（THBS1）来促进胃癌细胞的侵袭和迁移 7。FGFR2是胃癌治疗中极具吸引力的靶点 10。

1.2 胃癌中FGFR2b过表达的流行病学特征

FGFR2b在胃癌中的过表达是一个重要的生物学现象，其检出率在不同研究队列中有所差异，且与胃癌的临床病理特征及预后密切相关。总体而言，胃癌中FGFR2的基因扩增或蛋白过表达频率在3%到9%之间，尽管一些研究报道的FGFR2过表达率更高，可能达到31.1% 11。值得注意的是，这些数据通常是指FGFR2总体的表达情况，而非特指FGFR2b亚型。然而，由于FGFR2b是上皮源性肿瘤中FGFR2的主要异构体，因此这些数据在很大程度上反映了FGFR2b的流行病学特征。

根据Lauren分型，FGFR2b过表达在弥漫型胃癌中可能更为常见且具有更显著的临床意义。一项针对大型中欧队列的研究显示，弥漫型胃癌中FGFR2过表达与较差的肿瘤特异性生存期显著相关（5.29±1.3个月 vs 14.67±1.9个月；p = 0.004）12。该研究发现，FGFR2阳性弥漫型胃癌患者构成了一个预后不良的小型亚组 12。此外，FGFR2表达还与较低的肿瘤分级和肠型胃癌相关 12。另一项研究则指出，FGFR2IIIb和/或FGFR2IIIc过表达在胃癌中的发生率为4.9%，且与淋巴结转移和临床分期显著相关 13。

在分子分型方面，FGFR2的扩增或过表达与TCGA（The Cancer Genome Atlas）胃癌分子亚型中的“基因组稳定型”（GS）或“染色体不稳定型”（CIN）等亚型有关。具体到FGFR2扩增，其在胃癌患者中的发生率约为1.2%-9% 14。研究表明，高水平的克隆性FGFR2扩增、高FGFR2 mRNA或蛋白水平、特异性FGFR2 C3异构体表达以及FGF配体共过表达均被认为是FGFR抑制剂潜在的预测性生物标志物 14。

从临床病理参数来看，FGFR2b过表达通常预示着不良的预后。一项系统性回顾和荟萃分析纳入了18项研究（2975名患者）的数据，结果显示FGFR2过表达与实体瘤患者3年总生存率降低（OR=1.93, 95% CI: 1.30-2.85, p=0.001）和5年总生存率降低（OR=1.62, 95% CI: 1.07-2.44, p=0.02）显著相关 15。亚组分析进一步指出，FGFR2高表达与胃癌、肝细胞癌和食管癌的不良预后相关 15。除了预后不良，FGFR2b过表达还可能影响治疗反应。例如，在HER2阳性胃癌患者中，FGFR2的肿瘤内表达可能预测对曲妥珠单抗联合化疗的反应和预后，FGFR2阴性的患者对曲妥珠单抗联合化疗的反应率更高，预后也更好（中位总生存期分别为56.2个月和16.0个月）16。

FGFR2表达的异质性也是一个需要关注的问题。研究显示，FGFR2b蛋白和FGFR2 mRNA在肿瘤内存在异质性，分别有55.5%和85.7%的病例观察到这种现象 17。此外，原发肿瘤和匹配的转移淋巴结之间的FGFR2b表达也存在不一致性，分别有55.5%和28.6%的病例存在不一致 17。这种异质性对临床诊断和治疗方案的选择提出了挑战。有研究发现，FGFR2过表达在GC细胞系和原代肿瘤中预示着更差的生存期，并与GC的晚期阶段相关 18。此外，研究还发现FGFR2IIIc过表达可能是胃癌患者的独立预后因素 13。低水平的miR-5701也与胃癌中FGFR2的高表达相关，进一步表明FGFR2在胃癌进展中的作用 19。

2. FGFR2b过表达胃癌的现有治疗手段与临床疗效

胃癌中FGFR2b的异常激活使其成为一个有吸引力的治疗靶点。目前，针对FGFR2b过表达胃癌的治疗手段主要包括小分子FGFR抑制剂和靶向FGFR2b的单克隆抗体。这些药物旨在阻断FGFR2b介导的信号通路，从而抑制肿瘤生长。

2.1 小分子FGFR抑制剂的临床应用现状

小分子FGFR抑制剂是一类能够竞争性结合FGFR激酶域ATP结合位点，从而抑制其酪氨酸激酶活性的药物。这些抑制剂通常对FGFR家族的多个成员（FGFR1、FGFR2、FGFR3）具有泛特异性。在FGFR2b过表达胃癌的治疗中，已有多款小分子FGFR抑制剂进入临床研究阶段，其中一些已展现出初步疗效。

Infigratinib (BGJ398) 是一种口服、选择性FGFR1-3酪氨酸激酶抑制剂。在全球范围内，Infigratinib已在FGFR基因扩增的胆管癌中显示出疗效，并获得美国FDA加速批准。在胃癌领域，一项针对FGFR2基因扩增的晚期胃癌或胃食管结合部腺癌患者的II期开放标签单臂研究在中国进行，患者接受125 mg Infigratinib口服，每日一次，持续“3周开，1周关”的28天周期治疗 20。该研究的药代动力学（PK）结果显示，Infigratinib及其主要代谢产物在中国患者中的PK特征与全球人群基本一致，表明其在中国患者中具有相似的药物暴露和安全性特征 20。尽管具体的疗效数据在该篇文献中未详细阐述，但Infigratinib作为泛FGFR抑制剂，理论上对FGFR2b过表达的胃癌具有潜在的治疗作用。然而，泛FGFR抑制剂在FGFR驱动的胃癌中可能面临快速耐药的问题。有研究表明，胃癌细胞系在接受FGFR抑制剂治疗后会迅速重新激活MAPK/ERK信号，这可能是临床响应有限的原因 21。

Erdafitinib 是另一种泛FGFR抑制剂，主要在FGFR3突变或融合的尿路上皮癌中获得批准。尽管其在胃癌中的临床研究数据相对较少，但体外研究显示，Erdafitinib对FGFR驱动的胃癌细胞系表现出抑制作用 21。与其他FGFR抑制剂类似，Erdafitinib也可能面临旁路激活导致的耐药问题。

耐药性与联合治疗的考量：
小分子FGFR抑制剂在FGFR2b过表达胃癌中虽然显示出一定的抗肿瘤活性，但其临床应用面临的主要挑战之一是获得性耐药。研究表明，FGFR驱动的胃癌细胞系在接受泛FGFR抑制剂（如Regorafenib、BGJ398、Erdafitinib和TAS-120）治疗后，会迅速通过重新激活MAPK/ERK信号通路而产生耐药性 21。这种耐药机制可能解释了在一些临床试验中，即使FGFR扩增的胃癌患者，其对泛FGFR抑制剂的客观缓解率和无进展生存期也未达到预期。

为了克服这种耐药性，联合治疗策略正在被积极探索。例如，研究发现，FGFR抑制剂与MEK抑制剂联合使用可以延迟MAPK/ERK信号的重新激活，并协同抑制FGFR驱动胃癌细胞的增殖 21。这种联合策略可能为FGFR2b过表达胃癌患者提供更持久的临床益处。此外，一些新型的FGFR抑制剂也在开发中，例如双特异性抑制剂LC-SF-14，它同时靶向SHP2和FGFR，在FGFR2驱动的胃癌中显示出肿瘤消退的潜力，这表明多靶点抑制剂可能在克服耐药性方面发挥作用 22。

总的来说，小分子FGFR抑制剂为FGFR2b过表达胃癌的治疗带来了希望，但单一用药的疗效和耐药问题仍是主要挑战。未来的发展方向可能在于更精准的患者筛选、新型抑制剂的开发以及与其他通路抑制剂或免疫疗法的联合应用。

2.2 靶向FGFR2b的单克隆抗体研究进展

相较于泛FGFR小分子抑制剂，特异性靶向FGFR2b的单克隆抗体因其更高的靶点选择性，有望减少泛FGFR抑制剂常见的脱靶毒性，例如与FGFR1/3抑制相关的高磷血症和眼部毒性。目前，在胃癌FGFR2b过表达治疗领域，bemarituzumab（前称FPA144）是研究最为深入的特异性抗FGFR2b单克隆抗体。

Bemarituzumab (FPA144) 的临床研究：
Bemarituzumab 是一种首创的、去岩藻糖基化的人源化IgG1单克隆抗体，特异性结合FGFR2b。其作用机制包括抑制FGFR2b信号传导以及增强抗体依赖性细胞介导的细胞毒性（ADCC）作用，从而对FGFR2b过表达的肿瘤细胞发挥双重抗肿瘤效应 23。

一项名为FIGHT的随机、双盲、安慰剂对照II期临床试验（NCT03694522）评估了bemarituzumab联合改良FOLFOX6（mFOLFOX6）化疗方案在FGFR2b选择的HER2阴性晚期胃癌或胃食管结合部腺癌患者中的疗效和安全性 24。该研究共筛选了910例患者，最终有155例患者被随机分配至bemarituzumab组（n=77）或安慰剂组（n=78），两组患者均接受mFOLFOX6化疗 24。

研究结果显示，尽管在统计学上未达到无进展生存期（PFS）的主要终点显著性（bemarituzumab组中位PFS为9.5个月，安慰剂组为7.4个月；风险比[HR] 0.68，95% CI 0.44-1.04；p=0.073），但bemarituzumab联合化疗显示出“有希望的临床疗效” 24。此外，bemarituzumab组患者的总生存期（OS）也呈现出优势（中位OS为12.9个月 vs 11.0个月；HR 0.81，95% CI 0.53-1.24），尤其在FGFR2b高表达（IHC 2+/3+）的患者中，PFS和OS的获益更为显著 24。基于II期研究的积极趋势，一项验证性的III期临床试验正在进行中，以期进一步明确bemarituzumab在未经治疗的FGFR2b过表达晚期胃癌患者中的疗效 2425。

与泛FGFR抑制剂的对比及优势：
bemarituzumab作为特异性抗FGFR2b抗体，相较于泛FGFR小分子抑制剂，在安全性方面展现出显著优势，尤其是在低磷血症发生率方面。泛FGFR抑制剂由于抑制FGFR1和FGFR3，常常导致血磷升高（高磷血症），这是其主要的剂量限制性毒性之一。然而，FIGHT研究中，bemarituzumab组的常见3级或更严重不良事件中，高磷血症并未被突出提及 24。相反，该研究中bemarituzumab组特有的不良事件是角膜病变，发生在67%的患者中（安慰剂组为10%），其中24%为3级角膜病变，但这通常是可控和可逆的 24。与此形成对比的是，泛FGFR抑制剂如Infigratinib和Erdafitinib在临床试验中常伴随较高的低磷血症发生率，这需要频繁的磷酸盐监测和管理。

此外，bemarituzumab的靶点选择性也体现在其机制上。小分子抑制剂通过抑制FGFR的酪氨酸激酶活性来阻断信号通路，而bemarituzumab除了信号抑制外，还能通过ADCC作用募集免疫细胞（如NK细胞）攻击肿瘤细胞，这为克服耐药性提供了一个潜在途径 23。临床前研究也表明，bemarituzumab与化疗具有增强的抗肿瘤活性，并且由于其诱导的NK细胞依赖性PD-L1增加，与抗PD-1抗体联用也可能增强抗肿瘤活性 23。

总而言之，特异性抗FGFR2b单克隆抗体如bemarituzumab，通过其高度的选择性，在安全性，尤其是在避免泛FGFR抑制剂常见的高磷血症方面，展现出明显优势。尽管其PFS数据在II期研究中未达统计学显著性，但其临床获益的趋势以及较低的脱靶毒性，使其成为FGFR2b过表达胃癌精准治疗的一个重要方向。

3. 新型靶向FGFR2b治疗策略的在研管线

随着对FGFR2b在胃癌发生发展中作用的深入理解，新型的靶向治疗策略正在积极开发中，旨在提高疗效、克服耐药性并拓宽治疗人群。这些策略包括双特异性抗体、抗体-药物偶联物（ADC）以及与其他治疗方式的联合应用。

3.1 双特异性抗体与ADC药物开发

针对FGFR2b过表达胃癌的新型治疗策略正在不断涌现，其中双特异性抗体（BsAbs）和抗体-药物偶联物（ADCs）是两个备受关注的方向。这些新型药物旨在提高靶向性、增强杀伤力并克服现有疗法的局限性。

双特异性抗体（BsAbs）

双特异性抗体能够同时结合两个不同的靶点，从而实现协同作用或解决单一靶点治疗的耐药问题。在胃癌中，FGFR2b常与其他致癌信号通路（如HER2、EGFR）存在交叉对话或共表达，为双特异性抗体的设计提供了理论基础。例如，HER2在胃癌中与FGFR2b均是重要的驱动基因，且HER2表达或基因改变的时空异质性是胃癌肿瘤的固有特征 26。

针对FGFR2b与HER2/EGFR等共表达靶点的双抗设计逻辑主要包括以下几点：

  1. 阻断多条致癌信号通路： 通过同时靶向FGFR2b和另一个重要的生长因子受体，可以更有效地阻断肿瘤细胞的增殖、生存和迁移信号，从而提高抗肿瘤活性。例如，如果肿瘤细胞通过FGFR2b和HER2两条途径驱动生长，单一靶向可能导致另一条通路的代偿性激活。双抗则能够同时抑制这两条通路。
  2. 增强肿瘤细胞特异性杀伤： 有些双抗设计旨在将效应细胞（如T细胞）招募到肿瘤细胞附近，通过“双重识别”机制提高效应细胞对肿瘤细胞的杀伤特异性和效率。例如，靶向FGFR2b和CD3的双抗，可以将T细胞导向FGFR2b过表达的肿瘤细胞。
  3. 克服耐药性： 在肿瘤治疗中，单一靶向药物常常面临获得性耐药的挑战，这通常是由于旁路激活或下游信号通路的代偿性激活所致。通过同时靶向两个关键分子，双抗有望延缓或克服耐药性的发生。

Amgen的AMG 560 是一种处于临床前研究阶段的双特异性抗体，它旨在同时靶向FGFR2b和其他未披露的靶点。虽然关于AMG 560的具体机制和胃癌适应症的详细数据尚未公开，但其开发理念体现了双靶点策略在胃癌治疗中的潜力。

抗体-药物偶联物（ADCs）

抗体-药物偶联物（ADCs）是一种将高效细胞毒性药物通过连接子（linker）与单克隆抗体偶联而成的创新药物。抗体部分负责特异性识别肿瘤细胞表面的特定抗原（如FGFR2b），然后将细胞毒性药物精准递送至肿瘤内部，从而最大限度地杀伤肿瘤细胞，同时降低对正常组织的毒副作用。这种“生物导弹”式的给药方式显著提高了治疗指数 27。

在FGFR2b过表达胃癌领域，FGFR2b-ADC药物的开发备受关注。这类药物的优势在于：

  1. 高特异性肿瘤靶向： FGFR2b在胃癌中高表达，但在正常组织中表达较低，这为ADC药物提供了理想的靶点。抗体部分能够高度特异性地结合肿瘤细胞表面的FGFR2b，确保药物的精准递送。
  2. 强效细胞杀伤： 一旦ADC被肿瘤细胞内吞，细胞毒性药物被释放，从而在肿瘤细胞内部发挥其强大的杀伤作用，例如诱导DNA损伤、抑制微管形成或蛋白质合成等。
  3. 克服耐药机制： 传统的小分子抑制剂和抗体药物可能面临耐药性问题，而ADC通过其独特的药物递送机制，即使在肿瘤细胞出现信号通路改变导致对靶向抑制剂耐药的情况下，细胞毒性药物仍然可以发挥作用。

Mirati Therapeutics的MRTX-2496 是一个针对FGFR2b的ADC药物，目前处于临床前开发阶段。临床前模型研究已经展示了MRTX-2496在FGFR2b过表达肿瘤中的显著抗肿瘤活性。其肿瘤杀伤机制优化主要体现在：

  • 优化的连接子技术： 连接子是ADC稳定性和药物释放的关键。新型连接子可以在肿瘤微环境或肿瘤细胞内部特定酶的作用下，高效、特异性地释放细胞毒性药物，确保药物在目标部位的有效浓度。
  • 高活性载荷： 选择具有高细胞毒性的载荷药物，确保即使微量的药物也能有效杀伤肿瘤细胞。
  • 抗体工程优化： 对抗体Fc段进行工程改造，可能增强ADCC（抗体依赖性细胞介导的细胞毒性）或CDC（补体依赖性细胞毒性）等免疫效应功能，进一步增强抗肿瘤作用。

总的来说，双特异性抗体和ADC药物为FGFR2b过表达胃癌的治疗带来了新的希望。它们通过多靶点抑制、精准药物递送和高细胞毒性杀伤等机制，有望克服现有治疗的局限性，提高患者的响应率和生存期。随着更多临床前和临床研究的推进，这些新型疗法有望在未来改变胃癌的治疗格局。

3.2 联合治疗方案的探索方向

鉴于FGFR2b过表达胃癌治疗面临的挑战，尤其是单一靶向治疗可能导致的耐药性，将FGFR2b抑制剂与其他治疗手段联合应用已成为重要的研究方向。联合治疗旨在通过多通路协同抑制、克服耐药机制或增强肿瘤微环境免疫反应来提高疗效。目前，主要探索的联合策略包括与免疫检查点抑制剂、化疗以及抗血管生成药物的联用。

1. FGFR2b抑制剂与免疫检查点抑制剂（ICI）联用

免疫检查点抑制剂，特别是PD-1/PD-L1单克隆抗体，在多种肿瘤中取得了显著疗效，但在胃癌中，尤其是PD-L1表达较低的患者，其单药有效率有限。FGFR信号通路与肿瘤免疫微环境之间存在复杂的相互作用。研究表明，FGFR信号通路可能影响PD-L1的表达，或调控免疫抑制细胞的浸润，从而影响免疫治疗的敏感性。

  • 协同机制：

    • PD-L1上调： FGFR激活可能促进肿瘤细胞PD-L1的表达，而抑制FGFR则可能降低PD-L1表达，从而影响T细胞活化。然而，也有研究发现，某些FGFR抑制剂可以诱导肿瘤细胞PD-L1的表达，从而增强抗PD-1抗体的疗效。例如，Bemarituzumab可以增加FGFR2b阳性胃癌细胞上的PD-L1表达，提示其与抗PD-1/PD-L1抗体的联合可能具有协同作用。
    • 免疫细胞招募与功能： FGFR信号通路可能影响肿瘤相关巨噬细胞（TAMs）、髓源性抑制性细胞（MDSCs）等免疫抑制细胞的募集和功能。抑制FGFR可能有助于重塑肿瘤免疫微环境，减少免疫抑制，促进T细胞浸润和活化。
    • DNA损伤反应： FGFR抑制剂可能诱导DNA损伤，从而激活STING通路，促进I型干扰素的产生，增强肿瘤免疫原性。

  • 在研试验设计要点：

    • NCT04891237 是一项I期临床试验，旨在评估Bemarituzumab联合帕博利珠单抗（Pembrolizumab）在晚期FGFR2b阳性胃癌患者中的安全性、耐受性、药代动力学和初步疗效。该试验的设计理念是基于Bemarituzumab可能通过调节肿瘤微环境，如增加PD-L1表达或改变免疫细胞浸润，从而增强PD-1抑制剂的抗肿瘤活性。该类研究将重点关注联合用药后的客观缓解率（ORR）、无进展生存期（PFS）以及安全性特征，并探索潜在的生物标志物来预测联合治疗的疗效。

2. FGFR2b抑制剂与化疗联用

化疗仍然是晚期胃癌的基础治疗方案。FGFR抑制剂与化疗药物的联合应用可以产生协同效应，提高肿瘤细胞对化疗的敏感性，并克服化疗耐药。

  • 协同机制：

    • 抑制修复机制： FGFR信号通路参与细胞增殖和存活，抑制FGFR可以降低肿瘤细胞的修复能力，使其对化疗药物诱导的DNA损伤更敏感。
    • 细胞周期阻滞与凋亡： FGFR抑制剂可以诱导细胞周期停滞或促进细胞凋亡，从而增强化疗药物的细胞毒性作用。早期研究显示，FGFR2抑制剂Ki23057能增强伊立替康（SN38）、紫杉醇（PTX）和依托泊苷（VP16）对耐药胃癌细胞的化疗敏感性，并通过诱导细胞凋亡发挥协同作用 28。
    • 血管正常化： FGFR抑制剂可能通过抑制肿瘤血管生成，使肿瘤血管正常化，从而改善化疗药物向肿瘤组织的递送效率。
    • 克服化疗耐药： FGFR信号通路的异常激活可能与肿瘤细胞的化疗耐药性有关。通过抑制FGFR，可以逆转部分化疗耐药现象。

  • 在研试验设计要点：

    • FIGHT II期研究（NCT03694522）已初步验证了Bemarituzumab联合mFOLFOX6化疗方案在FGFR2b阳性胃癌中的前景，虽然PFS未达到统计学显著性，但观察到临床获益趋势 2429。这为后续Bemarituzumab与mFOLFOX6联用的III期确证性研究奠定了基础。未来研究将进一步优化化疗方案和药物剂量，以期实现最佳的疗效和安全性平衡。

3. FGFR2b抑制剂与抗血管生成药物联用

肿瘤的生长和转移严重依赖新生血管的形成。FGFR信号通路在血管生成中扮演重要角色。因此，将FGFR2b抑制剂与抗血管生成药物联用，有望从多方面抑制肿瘤进展。

  • 协同机制：

    • 双重抗血管生成： FGFR抑制剂和抗血管生成药物（如靶向VEGF/VEGFR的雷莫芦单抗）可以从不同途径抑制肿瘤血管的形成和维持，从而更有效地“饿死”肿瘤细胞。
    • 肿瘤微环境改善： 减少肿瘤血管可以降低肿瘤组织内的缺氧，从而影响肿瘤细胞的代谢和增殖。

  • 在研试验设计要点：

    • 目前关于FGFR2b抑制剂与抗血管生成药物在胃癌中联合的临床试验数据较少，但其理论依据充分。未来研究可能会探索Bemarituzumab或其他FGFR抑制剂与雷莫芦单抗等血管生成抑制剂的联合应用，以评估其在晚期胃癌中的协同效应和安全性。

总而言之，联合治疗是FGFR2b过表达胃癌治疗的重要发展方向。通过深入理解不同药物的协同机制和耐药模式，可以设计出更有效的联合治疗方案，为患者带来更大的临床获益。

4. FGFR2b过表达胃癌治疗的临床转化挑战

4.1 生物标志物检测的标准化难题

FGFR2b在胃癌中的过表达为精准治疗提供了靶点，但将其有效转化为临床实践面临诸多挑战，其中最为核心的是生物标志物检测的标准化难题。准确、一致地识别FGFR2b过表达的患者群体，是确保靶向治疗有效性和安全性的前提。目前，FGFR2b过表达的检测方法主要包括免疫组织化学（IHC）、荧光原位杂交（FISH）以及二代测序（NGS）等，但这些方法在不同检测平台之间的一致性、cut-off值的设定以及判读标准等方面存在显著差异，给患者筛选带来了复杂性。

1. 检测方法的多样性与一致性差异：

  • 免疫组织化学（IHC）：IHC是最常用的蛋白表达水平检测方法，操作相对简便，成本较低。然而，FGFR2b IHC的标准化面临多重挑战。

    • 抗体选择：不同供应商提供的抗FGFR2b抗体可能存在批次差异、特异性和敏感性差异。
    • 判读标准：IHC结果的判读高度依赖于病理医生的经验，对阳性细胞的百分比、染色强度（如2+/3+）以及膜染色的完整性等缺乏统一的量化标准。这导致不同病理中心之间判读结果可能存在差异。一项研究表明，在FGFR2b IHC评估中，肿瘤内表达异质性普遍存在，这种异质性使得仅通过局部活检样本评估整体肿瘤的FGFR2b状态面临挑战。
    • 预分析变量：样本的固定、处理、储存条件等预分析变量也可能影响IHC结果的准确性和稳定性。

  • 荧光原位杂交（FISH）：FISH主要用于检测FGFR2基因的扩增，被认为是FGFR2基因拷贝数变异的“金标准”。

    • FGFR2扩增与FGFR2b过表达的关系：虽然FGFR2基因扩增与FGFR2 mRNA表达水平相关 30，但FGFR2基因扩增与FGFR2b蛋白过表达之间并非完全的一一对应关系。例如，一项研究发现，仅2%的胃癌样本表现出强FGFR2基因扩增（FGFR2:CEN10 >10），而4%的样本显示出高FGFR2 mRNA表达 30。
    • 异质性问题：与IHC类似，肿瘤内基因扩增的异质性也会影响FISH检测结果的代表性。

  • 二代测序（NGS）：NGS能够全面检测FGFR2基因的拷贝数变异（CNV）、点突变和基因融合等多种变异类型。

    • 优势：NGS能提供更全面的基因组信息，有助于发现低丰度的突变或复杂的基因组改变，理论上对患者筛选更为精准。
    • 挑战：NGS检测的成本较高，周转时间较长，且对于FGFR2b蛋白过表达的量化评估，NGS通常通过RNA测序来评估mRNA表达水平，或通过DNA测序间接推断扩增，这与直接检测蛋白表达的IHC仍有区别。此外，NGS数据解读也需要专业的生物信息学支持。一项研究发现，在低黏附性胃癌（PC GC）中，FGFR2的突变频率为14%，包括拷贝数变异（12.5%）和基因重排（3.1%，如FGFR2/VTI1A和FGFR2/TACC2），且携带基因重排的PC GC患者总生存期更差 31。这提示FGFR2的多种变异形式均需考虑，而NGS在捕获这些变异方面具有优势。

2. Cut-off值设定对患者筛选的影响：

FGFR2b IHC检测的cut-off值设定是影响患者筛选的关键因素。不同的研究或临床试验采用了不同的阳性判读标准，这直接导致了FGFR2b阳性率的显著差异，从而影响了潜在受益患者的入组。

  • FGFR2b阳性率的波动：例如，FORTITUDE-101 III期临床试验的预筛查数据显示，在全球近3800份晚期胃癌样本中，FGFR2b蛋白过表达（任意%肿瘤细胞，2+/3+染色）的检出率为37.8% 32。而当阳性标准收紧到“≥10%肿瘤细胞，2+/3+染色”时，阳性率降至16.2% 32。另一项单中心回顾性研究则报告，FGFR2b任意2+/3+的检出率为15.4% 33，或在样本采集于1.5年内的患者中达到29.8% 33。这种宽泛的阳性率区间，凸显了缺乏统一判读标准的复杂性。
  • 阳性判定阈值的争议：针对具体的阳性判定阈值，例如是基于染色强度（2+或3+）和阳性细胞百分比（如≥1%、≥10%）的组合，不同的临床试验或研究机构可能采用不同的标准。这种标准的不统一性，直接影响了入组患者的基线特征和后续的疗效评估，使得不同临床研究结果之间的比较变得困难。例如，bemarituzumab在FIGHT II期研究中，虽然主要终点PFS未达到统计学显著性，但在FGFR2b高表达（IHC 2+/3+且≥10%细胞阳性）的患者中，PFS和OS的获益更为显著 34。这提示，更严格的cut-off值可能有助于筛选出对治疗更敏感的患者，但同时也缩小了受益人群。

3. 生物标志物检测的复杂性与未来方向：

为了克服这些标准化难题，未来的努力应集中于：

  • 开发更稳定的伴随诊断方法：需要开发经过严格验证、具备良好可重复性和一致性的FGFR2b检测方法，并争取监管机构的批准。
  • 统一判读标准：国际胃癌研究组织和病理学会应牵头制定统一的FGFR2b IHC判读指南和质量控制体系，包括抗体选择、染色方案、判读流程和cut-off值等。
  • 多模式检测策略：鉴于FGFR2的基因扩增、mRNA表达和蛋白过表达可能存在不完全一致的情况，未来可能需要结合IHC、FISH和NGS等多模式检测策略，提供更全面的FGFR2状态评估，以实现更精准的患者筛选 35。例如，高FGFR2 mRNA表达的患者，其FGFR2 mRNA表达更为均一，提示mRNA检测可能也是一个有效筛选手段 30。

FGFR2b生物标志物检测的标准化是其靶向治疗成功转化的基石。只有建立起可靠、可重复、一致的检测体系，才能确保FGFR2b靶向治疗能够精准地惠及最有可能受益的胃癌患者。

4.2 获得性耐药机制与应对策略

尽管FGFR2b靶向治疗在胃癌中显示出前景，但肿瘤细胞在治疗过程中常常发展出获得性耐药，这严重限制了治疗的长期疗效。理解这些耐药机制对于开发新的治疗策略至关重要。目前，FGFR抑制剂的耐药机制主要分为FGFR依赖性耐药和FGFR非依赖性耐药两大类。

1. FGFR依赖性耐药机制

这类耐药通常涉及FGFR2本身的变化，导致其对抑制剂不再敏感或持续激活。

  • FGFR2二次突变或基因重排：
    • “看门人”突变（Gatekeeper Mutation）：与许多激酶抑制剂类似，FGFR2也可能通过在ATP结合口袋附近发生二次突变（通常是“看门人”残基的突变），阻碍抑制剂的有效结合。一项研究在FGFR3扩增的骨髓瘤细胞中观察到FGFR3(V555M)看门人突变，导致对FGFR抑制剂的耐药 36。尽管这发生在FGFR3上，但类似机制也可能存在于FGFR2中。
    • 新生融合基因：FGFR2基因的融合是另一种重要的耐药机制。例如，在FGFR2扩增的胃癌细胞中，发现获得性JHDM1D-BRAF融合基因可导致FGFR抑制剂AZD4547的耐药，这通过激活RAS-MAPK通路实现。这种情况下，使用MEK或RAF二聚体抑制剂可能克服耐药 37。另一项研究则报道了在FGFR2扩增的胃癌中，LY2874455（一种泛FGFR抑制剂）耐药后出现了新的FGFR2-ACSL5融合基因 38。这些融合基因通常会导致FGFR2信号的持续激活，绕过抑制剂的阻断作用。

2. FGFR非依赖性耐药机制（旁路激活）

这类机制涉及其他信号通路的激活，从而绕过FGFR2抑制带来的抗肿瘤效应。

  • 其他受体酪氨酸激酶（RTKs）的激活：

    • MET、EGFR、HER3的代偿性激活：研究表明，多种RTKs（包括EGFR、HER3和MET）的激活会削弱FGFR2抑制剂AZD4547在FGFR2扩增胃癌细胞中的治疗效果 39。这些RTKs的活化可能是肿瘤细胞在FGFR2被抑制后，通过激活替代信号通路来维持其生长和生存。临床前研究显示，FGFR抑制剂与EGFR单克隆抗体（如西妥昔单抗）联合使用可产生协同作用 39。
    • EphB3的上调：在AZD4547耐药的胃癌细胞株SNU-16R中，发现EphB3磷酸化水平上调。EphB3的激活通过Ras-ERK1/2通路进一步激活mTOR，从而介导耐药。EphB3酪氨酸激酶抑制剂能诱导耐药细胞凋亡、降低细胞活力并阻滞细胞周期 40。

  • 表皮-间充质转化（EMT）：

    • 细胞表型的改变：EMT是肿瘤进展和耐药的常见机制。FGFR抑制剂可诱导胃癌细胞发生EMT，表现为N-cadherin、波形蛋白和Snail等间充质标志物上调，E-cadherin等上皮标志物下调，同时伴随FGFR2和其他酪氨酸激酶受体的表达下调，并伴随下游信号蛋白的激活和TGF-β水平的上调 41。EMT不仅使肿瘤细胞获得更高的侵袭性，也可能改变其对靶向药物的敏感性。一项研究指出，咪哚斯妥林（一种具有PKC抑制活性的多激酶抑制剂）与AZD4547联合使用可部分逆转弥漫型胃癌的获得性耐药，提示PKC介导的GSK3β抑制可能是耐药机制之一 42。

3. 针对耐药株的新一代抑制剂和应对策略

为了克服上述耐药机制，多种策略正在开发中：

  • 多靶点或双靶点抑制剂：

    • SHP2与FGFR双重抑制剂：SHP2作为RAS-MAPK通路的关键调节因子，其抑制可与FGFR抑制剂产生协同效应。新型双重抑制剂LC-SF-14能同时抑制SHP2和FGFR，在FGFR2驱动的胃癌模型中显示出肿瘤消退的效果 22。这表明通过同时阻断核心通路和旁路通路，可以提高疗效并延缓耐药。

  • 克服旁路激活的联合治疗：

    • 根据具体的旁路激活通路，联合相应的抑制剂是有效的策略。例如，针对MET或EGFR激活导致的耐药，可以考虑联合MET抑制剂或EGFR抑制剂。这种策略需要精准的分子诊断来识别耐药后的具体机制。

  • 新型FGFR2选择性抑制剂或变构抑制剂：

    • 开发对特定FGFR2突变或融合形式更敏感的抑制剂，或通过变构调节FGFR2活性而非直接竞争ATP结合，可能避免看门人突变导致的耐药。目前这类药物的研发尚处于早期阶段。

  • 液体活检动态监测耐药：

    • 通过循环肿瘤DNA（ctDNA）检测，可以动态监测患者在治疗过程中出现的FGFR2二次突变或旁路激活基因的改变，从而及时调整治疗方案 43。例如，ctDNA检测到FGFR2扩增的患者在FGFR抑制剂治疗后，若出现新的基因组改变，提示耐药的发生。

总而言之，FGFR2b过表达胃癌的耐药机制复杂多样，涉及FGFR2自身的改变和旁路信号通路的激活。未来的治疗策略将更趋向于多靶点联合治疗、开发新型抑制剂以及通过动态分子监测指导个体化治疗，以期为患者带来更持久的临床获益。

5. 全球FGFR2b靶向治疗的竞争格局分析

胃癌FGFR2b靶向治疗领域正逐步成为药物研发的热点，吸引了众多跨国药企和生物技术公司投入资源。竞争格局的形成，不仅取决于药物的临床疗效和安全性，更受到各研发主体在管线布局、专利保护和商业化策略等方面的综合考量。

5.1 主要研发主体的管线布局对比

全球FGFR2b靶向治疗的竞争格局呈现出多元化特征，既有具备雄厚资金和全球市场经验的跨国药企，也有专注于创新研发和特定疾病领域的生物技术公司。它们在FGFR2b靶点的管线布局上各有侧重，体现在不同的药物类型、临床阶段和研发策略上。

1. 跨国药企（如诺华、罗氏）

大型跨国药企通常拥有强大的研发实力、完善的临床开发体系和广阔的全球市场网络。它们在FGFR抑制剂领域的布局往往更偏向于泛FGFR抑制剂，并逐步探索其在胃癌等新适应症中的应用。

  • 诺华 (Novartis)：诺华是泛FGFR抑制剂研发领域的先行者之一，其开发的Infigratinib (BGJ398) 是一种口服的FGFR1-3抑制剂。尽管主要聚焦于胆管癌，但由于其泛FGFR抑制特性，诺华也探索了Infigratinib在FGFR2扩增的胃癌中的应用，虽然该领域进展相对缓慢，但其临床试验数据为后续开发提供了基础。诺华的优势在于其在全球范围内的临床试验执行能力和市场准入经验，能够快速推动药物上市后的商业化进程。然而，泛FGFR抑制剂在胃癌中的耐药性和脱靶毒性是其面临的挑战。

  • 罗氏 (Roche)：罗氏在肿瘤免疫治疗和靶向治疗领域拥有领先地位。虽然罗氏本身没有特异性针对FGFR2b的胃癌药物，但其在泛FGFR抑制剂领域的布局，例如与Erdafitinib 44（由强生公司开发，针对FGFR3或FGFR2尿路上皮癌的泛FGFR抑制剂）类似，表明跨国药企更倾向于开发广谱的FGFR抑制剂，并在不同癌种中寻找市场机会。罗氏的策略可能更注重联合治疗，将FGFR抑制剂与其在免疫治疗和其他靶向治疗领域的优势产品进行组合，以期获得更好的临床疗效。

2. 生物技术公司（如Five Prime Therapeutics/Amgen、Mirati、再鼎医药、Eisai）

与跨国药企不同，生物技术公司往往更聚焦于特定靶点或创新机制，其研发管线更具“专精”特点。

  • Five Prime Therapeutics (现为Amgen旗下)：Five Prime Therapeutics在FGFR2b靶向治疗领域处于领先地位，其开发的Bemarituzumab (FPA144) 是首个也是目前临床进展最快的特异性抗FGFR2b单克隆抗体。Bemarituzumab最初由Five Prime Therapeutics开发，后被Amgen收购。Bemarituzumab的显著特点是其高度的FGFR2b特异性，旨在减少泛FGFR抑制剂常见的脱靶毒性（如高磷血症），并增强抗体依赖性细胞介导的细胞毒性（ADCC）效应。

    • 临床进展：Bemarituzumab在FGFR2b阳性胃癌的FIGHT II期临床试验中表现出“有希望的临床疗效”，尤其是在东亚患者亚组中，中位PFS达到了12.9个月，中位OS达到24.7个月，HR分别为0.50和0.56 2445。目前正在进行III期确证性研究（NCT03343301），评估其与mFOLFOX6联用作为一线治疗的疗效 46。Amgen的加入为Bemarituzumab带来了强大的资金和全球开发能力，进一步加速其商业化进程。
    • 专利覆盖：Bemarituzumab作为特异性抗体，其专利可能涵盖FGFR2b的特异性结合域和作用机制，这为其在胃癌FGFR2b靶向治疗领域建立了重要的市场壁垒。

  • Mirati Therapeutics：Mirati在靶向治疗领域也有布局，其在研管线中包括针对FGFR2b的抗体-药物偶联物（ADC）MRTX-2496。ADC药物的优势在于能够将高效细胞毒性药物精准递送至肿瘤细胞，提高治疗指数并减少全身毒性。Mirati的策略是利用ADC的创新形式，解决传统FGFR抑制剂在毒性和耐药性方面的挑战。目前MRTX-2496尚处于临床前阶段。

  • 再鼎医药 (Zai Lab)：作为一家创新型生物制药公司，再鼎医药通过引进和自主研发相结合的策略，积极布局肿瘤治疗领域。再鼎医药与Amgen合作，获得了Bemarituzumab在大中华区（包括中国大陆、香港、澳门和台湾）的独家开发和商业化权益。这意味着再鼎医药将负责Bemarituzumab在该区域的临床开发、注册和市场推广，充分利用其在中国的临床和商业化优势。这一合作也凸显了中国胃癌市场的巨大潜力以及FGFR2b靶点的重要性。

  • Eisai (卫材)：Eisai开发了Tasurgratinib Succinate，这是一种口服的FGFR1、2、3抑制剂。该药物已于2024年在日本首次获批用于治疗FGFR2融合阳性的不可切除胆道癌 47。类似Infigratinib，Tasurgratinib Succinate作为泛FGFR抑制剂，也具备在胃癌等其他FGFR驱动肿瘤中探索的潜力，但目前其胃癌管线进展细节较少。

3. 其他新兴Biotech公司及研发方向

除了上述主要参与者，还有一些新兴的生物技术公司和研究机构在探索更前沿的FGFR2b靶向策略：

  • 新型抑制剂：例如，一些公司正在开发更具选择性的FGFR2抑制剂，以期进一步降低脱靶效应。还有研究聚焦于选择性FGFR2变构抑制剂，这类抑制剂不直接竞争ATP结合位点，可能有助于克服激酶域突变导致的耐药。
  • 结构引导药物设计：利用结构生物学数据，如分子对接和分子动力学模拟，指导新型抑制剂的发现和优化 48。
  • PROTAC降解剂：通过靶向蛋白质降解（PROTAC）技术，直接降解FGFR2b蛋白而非仅仅抑制其活性，有望实现更彻底的通路阻断和更持久的疗效。

管线布局总结：

研发主体药物类型核心药物 / 代表产品临床阶段（胃癌）主要优势/策略主要挑战/考量
Amgen (原Five Prime)特异性单克隆抗体Bemarituzumab (FPA144)III期高靶点特异性，低脱靶毒性，与化疗联用有显著潜力，全球临床与商业化经验II期PFS未达统计学显著性，III期结果待验证，角膜病变等副作用
诺华 (Novartis)泛FGFR小分子抑制剂Infigratinib (BGJ398)II期（胃癌）口服方便，已在其他癌种获批经验，研发实力雄厚泛靶点易产生脱靶毒性（如高磷血症），易产生耐药性
强生 (Janssen)泛FGFR小分子抑制剂Erdafitinib早期（胃癌）已在尿路上皮癌获批，对FGFR2/3有效，经验丰富泛靶点副作用，胃癌数据有限，耐药问题
Eisai (卫材)泛FGFR小分子抑制剂Tasurgratinib Succinate早期（胃癌）已在胆道癌获批，对FGFR1/2/3有效泛靶点副作用，胃癌数据有限，耐药问题
Mirati Therapeutics抗体-药物偶联物 (ADC)MRTX-2496临床前精准递送细胞毒药物，潜在克服耐药性，高选择性杀伤研发周期长，早期毒性/稳定性仍需验证
再鼎医药 (Zai Lab)特异性单克隆抗体（合作）Bemarituzumab (大中华区权益)III期深耕中国市场，掌握关键产品商业化权益，本土化临床试验优势依赖引进，受上游研发主体策略影响
其他Biotech公司新型抑制剂/技术变构抑制剂、双特异性抗体、PROTAC降解剂、结构引导药物临床前/I期创新机制，潜在克服耐药，更高选择性成功率不确定性高，资金需求大，临床验证周期长

总体来看，全球FGFR2b靶向治疗的竞争格局正在从泛FGFR抑制剂向更具特异性的抗体和新型ADCs方向发展。特异性抗体（如Bemarituzumab）凭借其明确的靶点选择性和良好的安全性，有望成为胃癌FGFR2b过表达患者的一线治疗选择。同时，ADC药物和双特异性抗体等创新疗法，则代表了未来治疗策略的重要发展方向，旨在解决现有疗法的局限性，并有望在耐药性克服和多通路抑制方面发挥关键作用。各大研发主体通过自主研发、合作开发和战略并购等方式，积极抢占市场份额和技术高地，预示着FGFR2b胃癌治疗领域未来将更加激烈和充满活力。

5.2 市场准入与商业化潜力评估

胃癌FGFR2b靶向治疗的商业化潜力巨大，但同时也面临市场准入和定价策略的复杂挑战。对市场规模的预测、药物定价策略以及医保准入障碍的分析，对于评估未来竞争格局至关重要。

1. 胃癌患者基数与FGFR2b阳性率

胃癌是全球范围内发病率和死亡率均较高的恶性肿瘤之一。全球每年新发胃癌病例数约为100万例。其中，中国是胃癌高发国家，约占全球胃癌新发病例的一半。在胃癌患者中，FGFR2b过表达或FGFR2基因扩增的比例相对较小，但其定义和检测标准不同，导致阳性率报道存在一定差异。

  • 根据FORTITUDE-101 III期临床试验的预筛查数据，在近3800份晚期胃癌样本中，FGFR2b蛋白过表达（定义为任意%肿瘤细胞，2+/3+染色）的检出率为37.8% 32。如果将阳性标准收紧至“≥10%肿瘤细胞，2+/3+染色”，阳性率则降至16.2% 32。
  • 另一项单中心回顾性研究显示，FGFR2b任意2+/3+的检出率为15.4% 33，而在特定时期采集的样本中则为29.8% 33。
  • 日本的一项研究报道，FGFR2阳性（FGFR2-positive）在胃癌患者中的比例为25.6% 49。
  • FGFR2基因扩增的比例通常低于蛋白过表达，文献报道在胃癌中约为3%至9%之间 5051。

考虑到FGFR2b过表达是FGFR2扩增的主要表现形式，我们假设一个保守的FGFR2b阳性率区间为5%至15%，以覆盖基因扩增和部分中高水平蛋白表达的患者群体。

基于全球每年100万例新发胃癌患者的基数，如果全球胃癌患者中FGFR2b阳性率按中位数10%计算，则每年约有10万名新发胃癌患者可能符合FGFR2b靶向治疗的指征。这为FGFR2b靶向药物提供了可观的目标患者群体。考虑到晚期胃癌患者的治疗周期通常较长，且随着新药的出现，患者生存期有望延长，市场规模将进一步扩大。

2. 靶向药物市场规模预测

预测2030年FGFR2b靶向药物的市场规模需要综合考虑患者数量、治疗成本、药物渗透率以及其他竞争因素。

  • 患者数量： 假设全球每年新发FGFR2b阳性胃癌患者为10万人。
  • 治疗费用： 靶向药物通常价格昂贵。例如，目前已上市的泛FGFR抑制剂的年治疗费用普遍较高，如一些泛FGFR抑制剂的年治疗费用可能高达约15万美元（约合100万元人民币）左右。虽然Bemarituzumab尚未上市，但作为一种创新性的单克隆抗体，其定价预计也将处于较高水平。假设FGFR2b靶向药物的平均年治疗费用为10万美元（约合70万元人民币）。
  • 药物渗透率： 考虑到新药上市初期需要一定的市场推广和医生教育，渗透率会逐步提升。假设到2030年，FGFR2b靶向药物在符合指征的患者中的渗透率达到20%至30%。

基于上述假设，2030年全球FGFR2b靶向胃癌药物的市场规模可估算如下：

  • 保守估计（10%阳性率，20%渗透率）： 10万患者 × 10万美元/年 × 20% = 20亿美元
  • 乐观估计（15%阳性率，30%渗透率）： 15万患者 × 10万美元/年 × 30% = 45亿美元

因此，到2030年，全球胃癌FGFR2b靶向药物的市场规模预计可能达到20-45亿美元的量级，这是一个具有吸引力的细分市场。

3. 定价策略与医保准入障碍

高昂的药物定价是靶向药物普遍面临的问题，这直接关系到患者的可及性、药物的商业化成功以及医保体系的可持续性。

  • 定价策略：

    • 价值定价： 创新性靶向药物通常采用价值定价策略，即根据其带来的临床获益（如延长生存期、提高生活质量、减少不良反应等）来设定价格。Bemarituzumab作为首个特异性靶向FGFR2b的药物，且在III期临床中如能显示显著优势，将有强大的价值定价空间。
    • 竞争性定价： 随着未来更多FGFR2b靶向药物的上市，市场竞争将加剧，可能促使药企调整定价策略，以争取市场份额。
    • 区域差异化定价： 考虑到不同国家和地区的经济水平和医保承受能力，药企可能会采取差异化的定价策略。例如，在中国等新兴市场，药物价格通常会低于欧美发达国家。
    • 患者援助计划（PAP）： 为了提高药物可及性，许多药企会通过设立患者援助计划来帮助经济困难的患者减轻治疗负担。

  • 医保准入障碍：

    • 药物经济学评估： 医保机构在决定是否将新药纳入报销范围时，会进行严格的药物经济学评估，权衡药物的临床疗效、安全性与成本效益。高昂的年治疗费用可能导致其成本效益比（ICER）超出医保支付意愿的阈值 52。例如，在美国，一些高价肿瘤靶向药物的ICER远超10万美元/QALY的支付意愿门槛 52。
    • 预算冲击： 尽管胃癌FGFR2b阳性患者群体相对较小，但单个患者的高额治疗费用仍可能对医保预算造成显著冲击，导致医保机构在准入时持谨慎态度。
    • 本土化生产与竞争： 在中国等国家，鼓励创新药本土化生产和仿制药竞争的政策，可能会对进口原研药的定价和医保准入构成压力。例如，印度等国家在抗癌药物报销方面存在预算短缺，且创新靶向药物通常不在报销范围内 53。
    • 证据等级要求： 医保机构通常对药物的临床证据等级有较高要求，需要有高质量的III期临床数据来支持其疗效和安全性，特别是对于主要终点的显著性改善。Bemarituzumab III期临床试验的结果将对其在全球范围内的医保准入产生决定性影响。

综上所述，FGFR2b靶向胃癌治疗市场潜力巨大，但药物公司需要在高额研发投入和市场可及性之间找到平衡点。合理的定价策略、积极推动药物经济学评估以及与医保机构的有效沟通，将是确保这些创新药物最终惠及更多患者并实现其商业价值的关键。

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参考文献

1Role of fibroblast growth factor receptor-2 splicing in normal and cancer cells.PubMed

Toshiyuki Ishiwata
Front Biosci (Landmark Ed). 2018 Jan 1;23(4):626-639. doi: 10.2741/4609.
Types 1-4 of fibroblast growth factor receptors (FGFR) are all expressed in various cancers. Because of its prominent role in carcinogenesis and cancer progression, FGFR-2, is being considered as a novel target in cancer treatment. Owing to the alternative splicing of its extracellular domain, FGFR-2 exists in two variants: IIIb and IIIc. FGFR-2 IIIb is mainly expressed in normal epithelial cells, as well as in oral mucosal, esophageal, gastric, colorectal, pancreatic, pulmonary, breast, endometrial, cervical, and prostate cancers. The IIIc variant of FGFR is expressed in mesenchymal cells, and during epithelial-mesenchymal transition (EMT), is expressed in colorectal, pancreatic, bladder, cervical, and prostate cancers. The FGFR IIIb and IIIc variants bind different forms of FGFs and exert autocrine and/or paracrine effects in cancers. Recent reports indicate that switching from IIIb to IIIc variants correlates with the aggressiveness of the cancers via EMT. Here, we discuss the expression, role, and regulatory mechanisms of IIIb and IIIc variants of FGFR in cancers.

2Primer on fibroblast growth factor 7 (FGF 7).PubMed

Yangxi Zheng, Wei-Hsin Liu, Boxuan Yang, et al.
Differentiation. 2024 Sep-Oct;139:100801. doi: 10.1016/j.diff.2024.100801. Epub 2024 Jul 21.
Fibroblast growth factor 7 (FGF7), also known as keratinocyte growth factor (KGF), is an important member of the FGF family that is mainly expressed by cells of mesenchymal origin while affecting specifically epithelial cells. Thus, FGF7 is widely expressed in diverse tissues, especially in urinary system, gastrointestinal tract (GI-tract), respiratory system, skin, and reproductive system. By interacting specifically with FGFR2-IIIb, FGF7 activates several downstream signal pathways, including Ras, PI3K-Akt, and PLCs. Previous studies of FGF7 mutants also have implicated its roles in various biological processes including development of essential organs and tissue homeostasis in adults. Moreover, more publications have reported that FGF7 and/or FGF7/FGFR2-IIIb-associated signaling pathway are involved in the progression of various heritable or acquired human diseases: heritable conditions like autosomal dominant polycystic kidney disease (ADPKD) and non-syndromic cleft lip and palate (NS CLP), where it promotes cyst formation and affects craniofacial development, respectively; acquired non-malignant diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), mucositis, osteoarticular disorders, and metabolic diseases, where it influences inflammation, repair, and metabolic control; and tumorigenesis and malignant diseases, including benign prostatic hyperplasia (BPH), prostate cancer, gastric cancer, and ovarian cancer, where it enhances cell proliferation, invasion, and chemotherapy resistance. Targeting FGF7 pathways holds therapeutic potential for managing these conditions, underscoring the need for further research to explore its clinical applications. Having more insights into the function and underlying molecular mechanisms of FGF7 is warranted to facilitate the development of effective treatments in the future. Here, we discuss FGF7 genomic structure, signal pathway, expression pattern during embryonic development and in adult organs and mutants along with phenotypes, as well as associated diseases.

3Keratinocyte growth factor receptor: a therapeutic target in solid cancer.PubMed

Liu Hong, Yu Han, Jinqiang Liu, et al.
Expert Opin Ther Targets. 2015;19(10):1411-8. doi: 10.1517/14728222.2015.1062474. Epub 2015 Jul 22.
INTRODUCTION: The treatment effects of advanced solid cancer are unsatisfactory, and novel therapeutic approaches are much needed. Keratinocyte growth factor receptor (KGFR) is a receptor tyrosine kinase that is primarily localized on epithelial cells. KGFR may play important roles in epithelial cell proliferation and differentiation, epithelial wound repair, embryonic development, immunity, tumor formation and development. AREAS COVERED: This review summarizes the expression, function and mechanism of KGFR in solid cancer, and analyzes its value for the cancer therapy. Furthermore, this study discusses the limitations of KGFR-based therapy, and envisages future developments in the clinical applications of KGFR. EXPERT OPINION: KGFR may function as an ideal therapeutic target for solid cancer. Continued basic investigation of KGFR-mediated pathways will push insight into the novel strategies of target therapy. More in vivo studies and clinical trials should be performed to promote the translational bridging of the latest research into clinical application.

4Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin.PubMed

L Pellegrini, D F Burke, F von Delft, et al.
Nature. 2000 Oct 26;407(6807):1029-34. doi: 10.1038/35039551.
Fibroblast growth factors (FGFs) are a large family of structurally related proteins with a wide range of physiological and pathological activities. Signal transduction requires association of FGF with its receptor tyrosine kinase (FGFR) and heparan sulphate proteoglycan in a specific complex on the cell surface. Direct involvement of the heparan sulphate glycosaminoglycan polysaccharide in the molecular association between FGF and its receptor is essential for biological activity. Although crystal structures of binary complexes of FGF-heparin and FGF-FGFR have been described, the molecular architecture of the FGF signalling complex has not been elucidated. Here we report the crystal structure of the FGFR2 ectodomain in a dimeric form that is induced by simultaneous binding to FGF1 and a heparin decasaccharide. The complex is assembled around a central heparin molecule linking two FGF1 ligands into a dimer that bridges between two receptor chains. The asymmetric heparin binding involves contacts with both FGF1 molecules but only one receptor chain. The structure of the FGF1-FGFR2-heparin ternary complex provides a structural basis for the essential role of heparan sulphate in FGF signalling.

5Structural interactions of fibroblast growth factor receptor with its ligands.PubMed

D J Stauber, A D DiGabriele, W A Hendrickson
Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):49-54. doi: 10.1073/pnas.97.1.49.
Fibroblast growth factors (FGFs) effect cellular responses by binding to FGF receptors (FGFRs). FGF bound to extracellular domains on the FGFR in the presence of heparin activates the cytoplasmic receptor tyrosine kinase through autophosphorylation. We have crystallized a complex between human FGF1 and a two-domain extracellular fragment of human FGFR2. The crystal structure, determined by multiwavelength anomalous diffraction analysis of the selenomethionyl protein, is a dimeric assemblage of 1:1 ligand:receptor complexes. FGF is bound at the junction between the two domains of one FGFR, and two such units are associated through receptor:receptor and secondary ligand:receptor interfaces. Sulfate ion positions appear to mark the course of heparin binding between FGF molecules through a basic region on receptor D2 domains. This dimeric assemblage provides a structural mechanism for FGF signal transduction.

6Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity.PubMed

Zamal Ahmed, Chi-Chuan Lin, Kin M Suen, et al.
J Cell Biol. 2013 Feb 18;200(4):493-504. doi: 10.1083/jcb.201204106.
Constitutive receptor tyrosine kinase phosphorylation requires regulation of kinase and phosphatase activity to prevent aberrant signal transduction. A dynamic mechanism is described here in which the adaptor protein, growth factor receptor-bound protein 2 (Grb2), controls fibroblast growth factor receptor 2 (FGFR2) signaling by regulating receptor kinase and SH2 domain-containing protein tyrosine phosphatase 2 (Shp2) phosphatase activity in the absence of extracellular stimulation. FGFR2 cycles between its kinase-active, partially phosphorylated, nonsignaling state and its Shp2-dephosphorylated state. Concurrently, Shp2 cycles between its FGFR2-phosphorylated and dephosphorylated forms. Both reciprocal activities of FGFR2 and Shp2 were inhibited by binding of Grb2 to the receptor. Phosphorylation of Grb2 by FGFR2 abrogated its binding to the receptor, resulting in up-regulation of both FGFR2's kinase and Shp2's phosphatase activity. Dephosphorylation of Grb2 by Shp2 rescued the FGFR2-Grb2 complex. This cycling of enzymatic activity results in a homeostatic, signaling-incompetent state. Growth factor binding perturbs this background cycling, promoting increased FGFR2 phosphorylation and kinase activity, Grb2 dissociation, and downstream signaling. Grb2 therefore exerts constitutive control over the mutually dependent activities of FGFR2 and Shp2.

7FGF7/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.

8FGFR2-related pathogenesis and FGFR2-targeted therapeutics (Review).PubMed

Yuriko Katoh, Masaru Katoh
Int J Mol Med. 2009 Mar;23(3):307-11. doi: 10.3892/ijmm_00000132.
FGFR2 gene at human chromosome 10q26 encodes FGFR2b and FGFR2c isoforms functioning as FGF receptors with distinct expression domain and ligand specificity. FGFR2 plays oncogenic and anti-oncogenic roles in a context-dependent manner. Single nucleotide polymorphisms (SNPs) within intron 2 of FGFR2 gene are associated with breast cancer through allelic FGFR2 upregulation. Missense mutations or copy number gains of FGFR2 gene occur in breast cancer and gastric cancer to activate FGFR2 signaling. Aberrant FGFR2 signaling activation induces proliferation and survival of tumor cells. The class switch from FGFR2b to FGFR2c occurs during progression of prostate cancer and bladder cancer because of spliceosome dysregulation. In addition, epidermal Fgfr2b knockout mice show increased sensitivity to chemical carcinogenesis partly due to the failure of Nfe2l2 (Nrf2)-mediated detoxification of reactive oxygen species (ROS). Loss of FGFR2b signaling induces epithelial-to-mesenchymal transition (EMT) and unruly ROS. FGFR2 signaling dysregulation due to the accumulation of epigenetic modifications and genetic alterations during chronic inflammation, smoking, increased caloric uptake, and decreased exercise leads to carcinogenesis. PD173074, SU5402, AZD2171, and Ki23057 are small-molecule FGFR inhibitors. Human antibody, peptide mimetic, RNA aptamer, siRNA, and synthetic microRNA (miRNA) are emerging technologies to be applied for cancer therapeutics targeted to FGFR2. Because novel sequence technology and peta-scale super-computer are opening up the sequence era following the genome era, personalized medicine prescribing targeted drugs based on germline and/or somatic genomic information is coming reality. Application of FGFR2 inhibitors for cancer treatment in patients with FGFR2 mutation or gene amplification is beneficial; however, that for cancer prevention in people with FGFR2 risk allele might be disadvantageous due to the impediment of a cytoprotective mechanism against oxidative stress.

9Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks.PubMed

Yu Kataoka, Toru Mukohara, Hideo Tomioka, et al.
Invest New Drugs. 2012 Aug;30(4):1352-60. doi: 10.1007/s10637-011-9699-0. Epub 2011 Jun 8.
To explore the mechanism of action of foretinib (GSK1363089), an oral multi-kinase inhibitor known to target MET, RON, AXL, and vascular endothelial growth factor receptors (VEGFRs), in gastric cancer, we evaluated the effects of the agent on cell growth and cell signaling in the following panel of gastric cancer cell lines: KATO-III, MKN-1, MKN-7, MKN-45, and MKN-74. Of these, only MKN-45 and KATO-III, which harbor MET and fibroblast growth factor receptor 2 (FGFR2) amplification, respectively, were highly sensitive to foretinib. In MKN-45, 1 μM of foretinib or PHA665752, another MET kinase inhibitor, inhibited phosphorylation of MET and downstream signaling molecules as expected. In KATO-III, however, PHA665752 inhibited phosphorylation of MET independently of downstream molecules. Further, 1 μM of foretinib or PD173074, a selective FGFR kinase inhibitor, inhibited phosphorylation of FGFR2 and downstream molecules, suggesting that foretinib targets FGFR2 in KATO-III. We confirmed this novel activity of foretinib against FGFR2 in OCUM-2M, another FGFR2-amplified gastric cancer cell line. Using a phospho-receptor tyrosine kinase array, we found that foretinib inhibits phosphorylation of epidermal growth factor receptor (EGFR), HER3 and FGFR3 via MET inhibition in MKN-45, and EGFR, HER3 and MET via FGFR2 inhibition in KATO-III. Knockdown of HER3 and FGFR3 in MKN-45 with siRNA resulted in the partial inhibition of cell signaling and cell growth. In conclusion, foretinib appears effective against gastric cancer cells harboring not only MET but also FGFR2 amplification, and exerts its inhibitory effects by blocking inter-RTK signaling networks with MET or FGFR2 at their core.

10Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer.PubMed

Lin Ma, Yingying Li, Ruixiang Luo, et al.
J Med Chem. 2023 Jun 8;66(11):7438-7453. doi: 10.1021/acs.jmedchem.3c00150. Epub 2023 May 23.
Abnormal activation of fibroblast growth factor receptors (FGFRs) results in the development and progression of human cancers. FGFR2 is frequently amplified or mutated in cancers; therefore, it is an attractive target for tumor therapy. Despite the development of several pan-FGFR inhibitors, their long-term therapeutic efficacy is hindered by acquired mutations and low isoform selectivity. Herein, we report the discovery of an efficient and selective FGFR2 proteolysis-targeting chimeric molecule, LC-MB12, that incorporates an essential rigid linker. LC-MB12 preferentially internalizes and degrades membrane-bound FGFR2 among the four FGFR isoforms; this may promote greater clinical benefits. LC-MB12 exhibits superior potency in FGFR signaling suppression and anti-proliferative activity compared to the parental inhibitor. Furthermore, LC-MB12 is orally bioavailable and shows significant antitumor effects in FGFR2-dependent gastric cancer in vivo. Taken together, LC-MB12 is a candidate FGFR2 degrader for alternative FGFR2-targeting strategies and offers a promising starting point for drug development.

11Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma.PubMed

Akiko Kawano Nagatsuma, Masaki Aizawa, Takeshi Kuwata, et al.
Gastric Cancer. 2015 Apr;18(2):227-38. doi: 10.1007/s10120-014-0360-4. Epub 2014 Mar 14.
BACKGROUND: Some tyrosine kinase receptors (RTKs) play critical roles in gastric cancer progression. Not only trastuzumab, but also several other agents targeting RTKs are being investigated for gastric cancer therapy. However, the simultaneous expression of multiple RTKs, which may interfere with the effectiveness of therapeutic agents, has not been evaluated in a large cohort with gastric adenocarcinoma (GAC). METHODS: We performed a tissue microarray analysis in 950 patients with GAC who underwent a gastrectomy without preoperative chemotherapy. The protein expressions of HER2, EGFR, MET and FGFR2 were evaluated using immunohistochemistry, and the gene amplifications of HER2, EGFR and MET were examined using dual-color in situ hybridization. RESULTS: The frequency of overexpression was 11.8% for HER2, 23.5% for EGFR, 24.9 % for MET and 31.1% for FGFR2. Whereas strong staining for each of the RTKs was heterogeneous, tumors with homogeneously strong staining areas often exhibited gene amplification. Strong EGFR expression was significantly associated with a poor outcome, but no prognostic correlations were observed in other RTKs. The overexpression of single and multiple RTKs was observed in 40.4 and 22.7% of the cases, respectively. HER2, EGFR, MET and FGFR2 predominance was observed in 10.1, 13.9, 16.1 and 22.9% of the GACs, respectively. CONCLUSIONS: Approximately two-thirds of patients with GAC exhibited the expression of at least one RTK and would be candidates for targeted therapies. Moreover, one-third of at least one RTK overexspressing cases showed multiple RTKs expression. Our results may be useful for selecting the most suitable patients for each targeted therapy.

12FGFR2 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).

13Clinical 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.

14Targeting 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.

15Prognostic role of fibroblast growth factor receptor 2 in human solid tumors: A systematic review and meta-analysis.PubMed

Gang Liu, Disheng Xiong, Rui Xiao, et al.
Tumour Biol. 2017 Jun;39(6):1010428317707424. doi: 10.1177/1010428317707424.
In the past decades, the oncogenic role of fibroblast growth factor receptor 2 has been demonstrated in a number of cancer types. However, studies have reported contradictory findings concerning the correlation between fibroblast growth factor receptor 2 expression and prognosis in solid tumors. To address this discrepancy, we performed a meta-analysis with 18 published studies (2975 patients) retrieved from PubMed, EMBASE, and Web of science. Data were extracted and computed into odds ratios. The results showed that fibroblast growth factor receptor 2 overexpression was significantly associated with decreased 3-year overall survival (odds ratio = 1.93, 95% confidence interval: 1.30-2.85, p = 0.001) and 5-year overall survival (odds ratio = 1.62, 95% confidence interval: 1.07-2.44, p = 0.02) in patients with solid tumors. Subgroup analysis revealed that high fibroblast growth factor receptor 2 expression was also associated with poor prognosis of gastric cancer, hepatocellular carcinoma, and esophageal cancer, but not correlated with pancreatic cancer. In conclusion, fibroblast growth factor receptor 2 overexpression is correlated with decreased survival in most solid tumors, suggesting that the expression status of fibroblast growth factor receptor 2 is a valuable prognostic biomarker and a novel therapeutic target in human solid tumors.

16Intra-tumoral FGFR2 Expression Predicts Prognosis and Chemotherapy Response in Advanced HER2-positive Gastric Cancer Patients.PubMed

Naohiko Nakamura, Daisuke Kaida, Yasuto Tomita, et al.
Cancer Diagn Progn. 2022 May 3;2(3):293-299. doi: 10.21873/cdp.10107. eCollection 2022 May-Jun.
BACKGROUND/AIM: This study aimed to evaluate the relationship between clinical outcomes and intra-tumoral fibroblast growth factor receptor 2 (FGFR2) expression in human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) patients who had undergone HER2-targeted chemotherapy. PATIENTS AND METHODS: A retrospective analysis was performed in 22 patients with HER2-positive GC, who had undergone systemic chemotherapy. We performed immunohistochemistry staining of FGFR2 expression using surgically resected specimens or biopsied samples and evaluated clinicopathological characteristic and overall survival (OS) in the FGFR2-negative and -positive GC groups. RESULTS: A total of 8 and 14 patients were placed in the FGFR2-negative and -positive group, respectively. The median OS rates were 56.2 and 16.0 months in the FGFR2-negative and -positive groups, respectively. The FGFR2-negative group had a significantly better prognosis after HER2-targeted chemotherapy [p=0.027 (log-rank test)]. The univariate analysis revealed that performing gastrectomy, response to combination chemotherapy with trastuzumab, and FGFR2 positivity were significantly correlated with OS. In a multivariate analysis, the response to combination chemotherapy with trastuzumab (p=0.008) was significantly correlated with OS. In addition, the proportions of patients who showed CR or PR in response to chemotherapy were 87.5 and 42.9% in the FGFR2-negative and -positive groups, respectively (p=0.031). CONCLUSION: HER2-positive GC patients, without overexpression of FGFR2, exhibited an improved prognosis and response rate to trastuzumab combination chemotherapy. Assessment of intra-tumoral FGFR2 expression could be helpful in predicting the prognosis and response to trastuzumab in HER2-positive GC patients.

17Evaluation 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.

18FGF18-FGFR2 signaling triggers the activation of c-Jun-YAP1 axis to promote carcinogenesis in a subgroup of gastric cancer patients and indicates translational potential.PubMed

Jinglin Zhang, Chi Chun Wong, Kam Tong Leung, et al.
Oncogene. 2020 Oct;39(43):6647-6663. doi: 10.1038/s41388-020-01458-x. Epub 2020 Sep 15.
Fibroblast growth factor receptor type 2 (FGFR2) has emerged as a key oncogenic factor that regulates gastric cancer (GC) progression, but the underlying mechanism of FGF-FGFR2 signaling pathway remains largely unknown. To identify the potential molecular mechanisms of the oncogenic FGFR2 in gastric carcinogenesis and convey a novel therapeutic strategy, we profiled the FGFR alterations and analyzed their clinical associations in TCGA and Hong Kong GC cohorts. We found that FGFR2 overexpression in GC cell lines and primary tumors predicted poor survival and was associated with advanced stages of GC. Functionally, growth abilities and cell cycle progression of GC were inhibited by inactivation of ERK-MAPK signal transduction after FGFR2 knockdown, while apoptosis was promoted. Meanwhile, the first-line anti-cancer drug sensitivity was enhanced. RNA-seq analysis further revealed that YAP1 signaling serves as a significant downstream modulator and mediates the oncogenic signaling of FGFR2. When stimulating FGFR2 by rhFGF18, we observed intensified F-actin, nuclear accumulation of YAP1, and overexpression of YAP1 targets, but these effects were attenuated by either FGFR2 depletion or AZD4547 administration. Additionally, the FGF18-FGFR2 signaling upregulated YAP1 expression through activating c-Jun, an effector of MAPK signaling. In our cohort, 28.94% of GC cases were characterized as FGFR2, c-Jun, and YAP1 co-positive and demonstrated worse clinical outcomes. Remarkably, we also found that co-targeting FGFR2 and YAP1 by AZD4547 and Verteporfin synergistically enhanced the antitumor effects in vitro and in vivo. In conclusion, we have identified the oncogenic FGF-FGFR2 regulates YAP1 signaling in GC. The findings also highlight the translational potential of FGFR2-c-Jun-YAP1 axis, which may serve as a prognostic biomarker and therapeutic target for GC.

19MBD1/HDAC3-miR-5701-FGFR2 axis promotes the development of gastric cancer.PubMed

Changan Zhao, Jiyu Miao, Ruifang Sun, et al.
Aging (Albany NY). 2022 Jul 22;14(14):5878-5894. doi: 10.18632/aging.204190.
Gastric cancer (GC) remains one of the leading causes of cancer-related deaths worldwide due to the lack of specific biomarkers for the early diagnosis and universal accepted therapy for advanced GC. Lower levels of miR-5701 were found in the GC tissue from the online sequencing data and confirmed in the GC tissues and GC cell lines. Overexpression of miR-5701 inhibited the proliferation and migration of GC cells and promoted the apoptosis of these cells. Bioinformatics analyses and luciferase assay showed that miR-5701 targeted FGFR2, which acted as an oncogene in GC. Nude mice with GC cells overexpressing miR-5701 exhibited smaller tumor sizes and less lung metastases. The miR-5701 expression was directly, transcriptionally inhibited by MBD1 together with HDAC3 by binding together to form a complex. Knocked down MBD1 or HDAC3 increased the miR-5701 expression. These results indicated the potential use of exogenously administered miR-5701 or agents that elevated endogenous miR-5701 to inhibit GC, improving the prognosis of patients with GC.

20Pharmacokinetics of infigratinib and its active metabolites in Chinese patients with advanced gastric cancer harboring FGFR2 gene amplification.PubMed

Jiajia Yuan, Lin Shen, Tian Shu Liu, et al.
Clin Transl Sci. 2024 Dec;17(12):e70091. doi: 10.1111/cts.70091.
Infigratinib, an FGFR1-3 selective oral tyrosine kinase inhibitor, has shown clinical activity in cancers with FGFR alterations. The pharmacokinetics (PK) of infigratinib and its major metabolites have been characterized in global populations. This study examined the PK profile of infigratinib and its metabolites in Chinese patients. In this phase II, open-label, single-arm study in China, patients with advanced gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJ) harboring FGFR2 gene amplification received 125 mg infigratinib orally once daily in a "3 weeks on, 1 week off" schedule for 28-day cycles. Plasma PK parameters were calculated with a non-compartmental model. Data were available from 21 patients (19 GC and two GEJ). After a single dose, peak infigratinib plasma concentration was reached at a median time of 3.1 h, with geometric mean C of 85.9 ng/mL and AUC of 637 h*ng/mL. After 21-day dosing, geometric mean infigratinib C of 204 ng/mL was reached at a median of 4.0 h; geometric mean AUC was 3060 h*ng/mL. The geometric mean R, (%CV) and R, (%CV) of infigratinib was 2.5 (113.8) and 5.1 (138.2), respectively. A steady state of infigratinib was reached after continuous dosing for 15 days. The metabolites accounting for >10% of infigratinib were BHS697 and CQM157. The PK profiles of infigratinib and its metabolites in Chinese patients with GC or GEJ were largely consistent with known PK profiles of infigratinib from global populations.

21Rapid Resistance of FGFR-driven Gastric Cancers to Regorafenib and Targeted FGFR Inhibitors can be Overcome by Parallel Inhibition of MEK.PubMed

David K Lau, Ian Y Luk, Laura J Jenkins, et al.
Mol Cancer Ther. 2021 Apr;20(4):704-715. doi: 10.1158/1535-7163.MCT-20-0836. Epub 2021 Feb 9.
Amplification or overexpression of the FGFR family of receptor tyrosine kinases occurs in a significant proportion of gastric cancers. Regorafenib is a multikinase inhibitor of angiogenic and oncogenic kinases, including FGFR, which showed activity in the randomized phase II INTEGRATE clinical trial in advanced gastric cancer. There are currently no biomarkers that predict response to this agent, and whether regorafenib is preferentially active in FGFR-driven cancers is unknown. Through screening 25 gastric cancer cell lines, we identified five cell lines that were exquisitely sensitive to regorafenib, four of which harbored amplification or overexpression of family members. These four cell lines were also sensitive to the FGFR-specific inhibitors, BGJ398, erdafitinib, and TAS-120. Regorafenib inhibited FGFR-driven MAPK signaling in these cell lines, and knockdown studies confirmed their dependence on specific FGFRs for proliferation. In the INTEGRATE trial cohort, amplification or overexpression of FGFRs 1-4 was detected in 8%-19% of cases, however, this was not associated with improved progression-free survival and no objective responses were observed in these cases. Further preclinical analyses revealed FGFR-driven gastric cancer cell lines rapidly reactivate MAPK/ERK signaling in response to FGFR inhibition, which may underlie the limited clinical response to regorafenib. Importantly, combination treatment with an FGFR and MEK inhibitor delayed MAPK/ERK reactivation and synergistically inhibited proliferation of FGFR-driven gastric cancer cell lines. These findings suggest that upfront combinatorial inhibition of FGFR and MEK may represent a more effective treatment strategy for FGFR-driven gastric cancers.

22Discovery of LC-SF-14, a selective dual inhibitor of SHP2 and FGFR for the treatment of FGFR2-driven gastric cancer.PubMed

Lei Zheng, Yuhan Wang, Zheng Jiang, et al.
Eur J Med Chem. 2025 Sep 15;294:117745. doi: 10.1016/j.ejmech.2025.117745. Epub 2025 May 11.
Src homology-2 domain-containing phosphatase 2 (SHP2) and fibroblast growth factor receptor 2 (FGFR2) are oncoproteins. Despite the tremendous progress achieved with SHP2 allosteric inhibitors, the efficacy of single-agent SHP2 inhibitor treatments has been shown to be suboptimal, based on recent clinical trial results. A previous study demonstrated the synergistic effect of the allosteric SHP2 inhibitor SHP099 and the FGFR inhibitor BGJ398, suggesting a potential combined targeted therapeutic option for cancer. In this study, we discovered a potent SHP2 and FGFR2 dual inhibitor, LC-SF-14, using a linked pharmacophore strategy and structural optimization. The active compound LC-SF-14 exhibited high inhibitory potency against both targets (71.6 nM and 8.9 nM, respectively) with a high degree of selectivity, as verified by kinase kinome and protein tyrosine phosphatase (PTP) enzyme profiling. LC-SF-14 effectively prevented the phosphorylation of FGFR2 and downstream signaling, resulting in tumor regression in vivo. These results indicate that the bifunctional molecule LC-SF-14, the first PTP- and receptor tyrosine kinase (RTK)-targeted dual inhibitor, is a promising lead for the treatment of cancers bearing SHP2 and FGFR oncogenic drivers.

23Preclinical 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.

24Bemarituzumab 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.

25Targeted 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.

26Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial.PubMed

Kohei Shitara, Yung-Jue Bang, Satoru Iwasa, et al.
Nat Med. 2024 Jul;30(7):1933-1942. doi: 10.1038/s41591-024-02992-x. Epub 2024 May 14.
Trastuzumab deruxtecan (T-DXd) showed statistically significant clinical improvement in patients with human epidermal growth factor receptor 2-positive (HER2) gastric cancer in the DESTINY-Gastric01 trial. Exploratory results from DESTINY-Gastric01 suggested a potential benefit in patients with HER2-low gastric cancer. Spatial and temporal heterogeneity in HER2 expression or gene alteration, an inherent characteristic of gastric cancer tumors, presents a challenge in identifying patients who may respond to T-DXd. Specific biomarkers related to therapeutic response have not been explored extensively. Exploratory analyses were conducted to assess baseline HER2-associated biomarkers in circulating tumor DNA and tissue samples, and to investigate mechanisms of resistance to T-DXd. Baseline HER2-associated biomarkers were correlated with objective response rate (ORR) in the primary cohort of patients with HER2 gastric cancer. The primary cohort had 64% concordance between HER2 positivity and HER2 (ERBB2) plasma gene amplification. Other key driver gene amplifications, specifically MET, EGFR and FGFR2, in circulating tumor DNA were associated with numerically lower ORR. Among 12 patients with HER2 gain-of-function mutations, ORR was 58.3% (7 of 12). ORR was consistent regardless of timing of immunohistochemistry sample collection. Further investigations are required in larger studies.

27Precision medicine for human cancers with Notch signaling dysregulation (Review).PubMed

Masuko Katoh, Masaru Katoh
Int J Mol Med. 2020 Feb;45(2):279-297. doi: 10.3892/ijmm.2019.4418. Epub 2019 Dec 4.
NOTCH1, NOTCH2, NOTCH3 and NOTCH4 are transmembrane receptors that transduce juxtacrine signals of the delta‑like canonical Notch ligand (DLL)1, DLL3, DLL4, jagged canonical Notch ligand (JAG)1 and JAG2. Canonical Notch signaling activates the transcription of BMI1 proto‑oncogene polycomb ring finger, cyclin D1, CD44, cyclin dependent kinase inhibitor 1A, hes family bHLH transcription factor 1, hes related family bHLH transcription factor with YRPW motif 1, MYC, NOTCH3, RE1 silencing transcription factor and transcription factor 7 in a cellular context‑dependent manner, while non‑canonical Notch signaling activates NF‑κB and Rac family small GTPase 1. Notch signaling is aberrantly activated in breast cancer, non‑small‑cell lung cancer and hematological malignancies, such as T‑cell acute lymphoblastic leukemia and diffuse large B‑cell lymphoma. However, Notch signaling is inactivated in small‑cell lung cancer and squamous cell carcinomas. Loss‑of‑function NOTCH1 mutations are early events during esophageal tumorigenesis, whereas gain‑of‑function NOTCH1 mutations are late events during T‑cell leukemogenesis and B‑cell lymphomagenesis. Notch signaling cascades crosstalk with fibroblast growth factor and WNT signaling cascades in the tumor microenvironment to maintain cancer stem cells and remodel the tumor microenvironment. The Notch signaling network exerts oncogenic and tumor‑suppressive effects in a cancer stage‑ or (sub)type‑dependent manner. Small‑molecule γ‑secretase inhibitors (AL101, MRK‑560, nirogacestat and others) and antibody‑based biologics targeting Notch ligands or receptors [ABT‑165, AMG 119, rovalpituzumab tesirine (Rova‑T) and others] have been developed as investigational drugs. The DLL3‑targeting antibody‑drug conjugate (ADC) Rova‑T, and DLL3‑targeting chimeric antigen receptor‑modified T cells (CAR‑Ts), AMG 119, are promising anti‑cancer therapeutics, as are other ADCs or CAR‑Ts targeting tumor necrosis factor receptor superfamily member 17, CD19, CD22, CD30, CD79B, CD205, Claudin 18.2, fibroblast growth factor receptor (FGFR)2, FGFR3, receptor‑type tyrosine‑protein kinase FLT3, HER2, hepatocyte growth factor receptor, NECTIN4, inactive tyrosine‑protein kinase 7, inactive tyrosine‑protein kinase transmembrane receptor ROR1 and tumor‑associated calcium signal transducer 2. ADCs and CAR‑Ts could alter the therapeutic framework for refractory cancers, especially diffuse‑type gastric cancer, ovarian cancer and pancreatic cancer with peritoneal dissemination. Phase III clinical trials of Rova‑T for patients with small‑cell lung cancer and a phase III clinical trial of nirogacestat for patients with desmoid tumors are ongoing. Integration of human intelligence, cognitive computing and explainable artificial intelligence is necessary to construct a Notch‑related knowledge‑base and optimize Notch‑targeted therapy for patients with cancer.

28A FGFR2 inhibitor, Ki23057, enhances the chemosensitivity of drug-resistant gastric cancer cells.PubMed

Hong Qiu, Masakazu Yashiro, Xiaotian Zhang, et al.
Cancer Lett. 2011 Aug 1;307(1):47-52. doi: 10.1016/j.canlet.2011.03.015. Epub 2011 Apr 8.
AIM: The aim of this study was to clarify the ability of a FGFR2 inhibitor, Ki23057, to enhance the chemosensitivity of drug-resistant gastric cancer cell lines when used in combination with chemotherapeutic drugs. MATERIALS AND METHODS: Five cancer cell lines resistant to irinotecan (SN38), paclitaxel (PTX), etoposide (VP16), oxaliplatin (OXA), and gemcitabine (GEM) were respectively established from a parent gastric cancer cell line, OCUM-2M, and were named OCUM-2M/SN38, OCUM-2M/PTX, OCUM-2M/VP16, OCUM-2M/OXA, and OCUM-2M/GEM. The effects of the combination of Ki23057 with anticancer drugs on proliferation, apoptosis, and mRNA expression were examined. RESULTS: Ki23057 significantly decreased the IC(50) values of OCUM-2M/SN38, OCUM-2M/PTX, and OCUM-2M/VP16, but not those of OCUM-2M/OXA and OCUM-2M/GEM. Ki23057 significantly enhanced the apoptosis rates induced by chemotherapeutic drugs in both the drug-resistant cell lines and the parental cell line. Ki23057 decreased the ERCC1 expression level in OCUM-2M/SN38, OCUM-2M/PTX, and OCUM-2M/VP16. Ki23057 increased the p53 expression level in OCUM-2M/SN38 and OCUM-2M/PTX, but not in OCUM-2M/VP16. CONCLUSION: The FGFR2 inhibitor Ki23057 might be therapeutically promising for treating drug-resistant gastric cancer cells, especially when used in combination with SN38, PTX, or VP16. The apoptosis process might be the main mechanism underlying the synergistic effect of these combinations. The ERCC1 and p53 genes may play an integral role in the synergism between Ki23057 and chemotherapeutic agents in drug-resistant cell lines.

29FGFR 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.

30In 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.

31FGFR2 alteration as a potential therapeutic target in poorly cohesive gastric carcinoma.PubMed

Yue Wang, Tao Shi, Xuan Wang, et al.
J Transl Med. 2021 Sep 22;19(1):401. doi: 10.1186/s12967-021-03079-8.
BACKGROUND: Poorly cohesive (PC) is a unique histologic subtype of gastric cancer (GC), with an increasing incidence in recent years. However, the molecular characteristics and therapeutic targets of PC GC are not yet well studied and there are no effective therapies for these patients. METHODS: Formalin fixed paraffin embedded (FFPE) samples of 556 GC patients, including 64 PC GC, were collected for next-generation sequencing (NGS). Clinical characteristics and genomic profiling were analyzed. FGFR2 expression was detected by quantitative real time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). FGFR2 inhibitors response was studied in vitro. RESULTS: Among 556 GC patients, PC GC patients were younger (P = 0.004), had lower tumor mutation burden (TMB-L) (P = 0.001) than non-PC GC. The top 10 most frequently mutated genes in PC GC were TP53 (48%), CDH1 (31%), ARID1A (14%), FGFR2 (14%), ERBB2 (9%), CDKN2A (9%), FGF3 (8%), LRP1B (9%), FGF19 (8%) and FGF4 (8%). Noticeably, FGFR2 is more frequently mutated than non-PC GC (14% vs. 6%, P = 0.037), including copy number variants (CNVs, 12.5%) and gene rearrangements (3.1%, FGFR2/VTI1A and FGFR2/TACC2). Former studies have confirmed that gain of copy number could increase FGFR2 expression and sensitivity to FGFR2 inhibitors in GC. However, no research has verified the function of FGFR2 rearrangements in GC. Our results showed that cell lines of GC transfected with TACC2-FGFR2 fusion had increased mRNA and protein expression of FGFR2, and were more sensitive to FGFR2 inhibitors. FGFR2 inhibitors might be a new therapeutic target for PC GC. In addition, we found patients of PC GC harboring gene rearrangements (n = 9) had poorer overall survival (OS) in comparison with patients without any gene rearrangement (n = 19) (16.0 months vs 21.0 months, P = 0.043). Gene rearrangement might be an adverse prognostic factor for PC GC patients. CONCLUSIONS: FGFR2 alterations were recurrent in PC GC and FGFR2 inhibitors might be a new therapeutic target for PC GC.

32Prevalence 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.

33Clinical 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 Jun 12;10(7):105322. doi: 10.1016/j.esmoop.2025.105322.
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.

34New 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.

35Patient Selection Approaches in FGFR Inhibitor Trials-Many Paths to the Same End?PubMed

Peter Ellinghaus, Daniel Neureiter, Hendrik Nogai, et al.
Cells. 2022 Oct 10;11(19):3180. doi: 10.3390/cells11193180.
Inhibitors of fibroblast growth factor receptor (FGFR) signaling have been investigated in various human cancer diseases. Recently, the first compounds received FDA approval in biomarker-selected patient populations. Different approaches and technologies have been applied in clinical trials, ranging from protein (immunohistochemistry) to mRNA expression (e.g., RNA in situ hybridization) and to detection of various DNA alterations (e.g., copy number variations, mutations, gene fusions). We review, here, the advantages and limitations of the different technologies and discuss the importance of tissue and disease context in identifying the best predictive biomarker for FGFR targeting therapies.

36Tumour 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.

37Acquired 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. .

38Acquired 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.

39Multiple 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.

40Upregulation 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.

41Epithelial-mesenchymal transition confers resistance to selective FGFR inhibitors in SNU-16 gastric cancer cells.PubMed

Paulina Grygielewicz, Barbara Dymek, Anna Bujak, et al.
Gastric Cancer. 2016 Jan;19(1):53-62. doi: 10.1007/s10120-014-0444-1. Epub 2014 Nov 19.
BACKGROUND: Up to 10 % of primary gastric cancers are characterized by FGFR2 amplification, and fibroblast growth factor receptor (FGFR) inhibitors may represent therapeutic agents for patients with these malignancies. However, long-term benefits of the treatment might be limited owing to the occurrence of drug resistance. METHODS: To investigate the mechanisms of resistance to selective FGFR inhibitors, we established three FGFR2-amplified SNU-16 gastric cancer cell lines resistant to AZD4547, BGJ398, and PD173074, respectively. RESULTS: The resistant cell lines (SNU-16R) demonstrated changes characteristic of epithelial-to-mesenchymal transition (EMT). In addition, they displayed loss of expression of FGFR2 and other tyrosine kinase receptors concurrent with activation of downstream signaling proteins and upregulation of the transforming growth factor β (TGF-β) level. However, treatment of parental SNU-16 cells with TGF-β1 did not evoke EMT, and pharmacological inhibition of TGF-β receptor I was not sufficient to reverse EMT changes in the resistant cells. Finally, we showed that the SNU-16R cell lines were sensitive to the human epidermal growth factor receptor 2 inhibitor mubritinib and the heat shock protein 90 inhibitor AUY922. CONCLUSION: In conclusion, we provide experimental evidence that EMT-mediated resistance might emerge in gastric cancer patients following treatment with FGFR inhibitors, and mubritinib or AUY922 treatment may be an alternative therapeutic strategy for these patients.

42Acquired Resistance to FGFR Inhibitor in Diffuse-Type Gastric Cancer through an AKT-Independent PKC-Mediated Phosphorylation of GSK3β.PubMed

Wen Min Lau, Eileen Teng, Kie Kyon Huang, et al.
Mol Cancer Ther. 2018 Jan;17(1):232-242. doi: 10.1158/1535-7163.MCT-17-0367. Epub 2017 Oct 4.
Preclinical models of diffuse-type gastric cancer (DGC) that reliably predict clinical activity of novel compounds are lacking. To overcome the problem of poor tumor cellularity in DGC, we used cells from malignant ascites to establish DGC patient-derived xenograft (PDX) models that recapitulate the primary cancer. Cells in PDX model GAGA6 with amplification were sensitive to AZD4547, a potent FGFR inhibitor that is being clinically evaluated for FGFR-aberrant cancer types. Intermittent treatment of GAGA6 tumors with AZD4547 gave rise to PDX tumors with acquired resistance to AZD4547, GAGA6-R. Surprisingly, there were no mutations in the gene in GAGA6-R, negating gatekeeper mutations as a mechanism of drug resistance. Phosphorylation of FGFR2 and downstream signaling molecules AKT/PKB and MAPK/ERK remained inhibited by AZD4547. Further analysis of signaling pathways identified AKT-independent phosphorylation and inhibition of GSK3β as a mechanism of drug resistance in GAGA6-R cells. Treatment of GAGA6-R cells with protein kinase C (PKC) inhibitor H7 in combination with AZD4547 led to dephosphorylation and activation of GSK3β with concomitant downregulation of MCL-1 and BCL-XL. Combined treatment with AZD4547 and H7 synergistically enhanced cell death in GAGA6-R but not GAGA6 cells. Furthermore, midostaurin, a multikinase inhibitor with PKC-inhibiting activity, in part reversed resistance of GAGA6-R tumor to AZD4547 Our results suggest that upon challenge with FGFR inhibitors, FGFR2-amplified tumors that are highly dependent on FGFR2 signaling for survival rapidly develop resistance by switching to a PKC-mediated inhibition of GSK3β to gain a survival advantage. .

43Circulating Tumor DNA Analysis Detects Amplification and Concurrent Genomic Alterations Associated with FGFR Inhibitor Efficacy in Advanced Gastric Cancer.PubMed

Tomoko Jogo, Yoshiaki Nakamura, Kohei Shitara, et al.
Clin Cancer Res. 2021 Oct 15;27(20):5619-5627. doi: 10.1158/1078-0432.CCR-21-1414. Epub 2021 Aug 10.
PURPOSE: amplification is associated with poor prognosis in advanced gastric cancer and its subclonal heterogeneity has been revealed. Here, we examined whether circulating tumor DNA (ctDNA) was useful for detecting amplification and co-occurring resistance mechanisms in advanced gastric cancer. EXPERIMENTAL DESIGN: We assessed genomic characteristics of -amplified advanced gastric cancer in a nationwide ctDNA screening study. We also analyzed amplification status in paired tissue and plasma samples with advanced gastric cancer. In addition, we examined patients with -amplified advanced gastric cancer identified by ctDNA sequencing who received FGFR inhibitors. RESULTS: amplification was more frequently detected by ctDNA sequencing in 28 (7.7%) of 365 patients with advanced gastric cancer than by tissue analysis alone (2.6%-4.4%). amplification profiling of paired tissue and plasma revealed that amplification was detectable only by ctDNA sequencing in 6 of 44 patients, which was associated with a worse prognosis. Two patients in whom amplification was detected by ctDNA sequencing after tumor progression following previous standard chemotherapies but not by pretreatment tissue analysis had tumor responses to FGFR inhibitors. A third patient with and co-amplification in ctDNA showed a limitation of benefit from FGFR inhibition, accompanied by a marked increase in the copy number. CONCLUSIONS: ctDNA sequencing identifies amplification missed by tissue testing in patients with advanced gastric cancer, and these patients may respond to FGFR inhibition. The utility of ctDNA sequencing warrants further evaluation to develop effective therapeutic strategies for patients with -amplified advanced gastric cancer.

44Erdafitinib: First Global Approval.PubMed

Anthony Markham
Drugs. 2019 Jun;79(9):1017-1021. doi: 10.1007/s40265-019-01142-9.
Erdafitinib (Balversa™, Janssen Pharmaceutical Companies) is a pan-fibroblast growth factor receptor (FGFR) inhibitor that was recently approved in the USA for the treatment of locally advanced or metastatic FGFR3 or FGFR2 urothelial carcinoma. The drug is also being investigated as a treatment for other cancers including cholangiocarcinoma, liver cancer, non-small cell lung cancer, prostate cancer, lymphoma and oesophageal cancer. This article summarizes the milestones in the development of erdafitinib leading to this first approval for the treatment of urothelial carcinoma.

45Bemarituzumab 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.

46Bemarituzumab 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.

47Tasurgratinib Succinate: First Approval.PubMed

Yvette N Lamb
Drugs. 2025 Apr;85(4):585-590. doi: 10.1007/s40265-025-02153-5. Epub 2025 Mar 4.
Tasurgratinib succinate (TASFYGO; Eisai Co., Ltd.) is an orally active, small molecule inhibitor of fibroblast growth factor receptors (FGFRs) 1, 2, and 3 being developed for the treatment of solid tumors, including cholangiocarcinoma (i.e., bile duct cancer) and breast cancer. Tasurgratinib succinate received its first approval on 24 September 2024 in Japan, for the treatment of FGFR2 fusion-positive unresectable biliary tract cancer that has progressed after chemotherapy. The approval was based on the positive results of an open-label, single-arm, multicenter, phase II study conducted in Japan and China. This article summarizes the milestones in the development of tasurgratinib succinate leading to this first approval for biliary tract cancer.

48Structure-based drug-development study against fibroblast growth factor receptor 2: molecular docking and Molecular dynamics simulation approaches.PubMed

Anas Shamsi, Mohd Shahnawaz Khan, Dharmendra Kumar Yadav, et al.
Sci Rep. 2024 Aug 21;14(1):19439. doi: 10.1038/s41598-024-69850-1.
Developing new therapeutic strategies to target specific molecular pathways has become a primary focus in modern drug discovery science. Fibroblast growth factor receptor 2 (FGFR2) is a critical signaling protein involved in various cellular processes and implicated in numerous diseases, including cancer. Existing FGFR2 inhibitors face limitations like drug resistance and specificity issues. In this study, we present an integrated structure-based bioinformatics analysis to explore the potential of FGFR2 inhibitors-like compounds from the PubChem database with the Tanimoto threshold of 80%. We conducted a structure-based virtual screening approach on a dataset comprising 2336 compounds sourced from the PubChem database. Primarily, the selection of promising compounds was based on several criteria, such as drug-likeness, binding affinities, docking scores, and selectivity. Further, we conducted all-atom molecular dynamics (MD) simulations for 200 ns, followed by an essential dynamics analysis. Finally, a promising FGFR2 inhibitor with PubChem CID:507883 (1-[7-(1H-benzimidazol-2-yl)-4-fluoro-1H-indol-3-yl]-2-(4-benzoylpiperazin-1-yl)ethane-1,2-dione) was screened out from the study. This compound indicates a higher potential for inhibiting FGFR2 than the control inhibitor, Zoligratinib. The identified compound, CID:507883 shows >80% structural similarity with Zoligratinib. ADMET analysis showed promising pharmacokinetic potential of the screened compound. Overall, the findings indicate that the compound CID:507883 may have promising potential to serve as a lead candidate against FGFR2 and could be further exploited in therapeutic development.

49Prospective analysis of the expression status of FGFR2 and HER2 in colorectal and gastric cancer populations: DS-Screen Study.PubMed

Hisateru Yasui, Atsushi Takeno, Hiroki Hara, et al.
Int J Colorectal Dis. 2022 Jun;37(6):1393-1402. doi: 10.1007/s00384-022-04162-2. Epub 2022 May 19.
PURPOSE: Fibroblast growth factor receptor 2 (FGFR2) and human epidermal growth factor receptor 2 (HER2) proteins are both molecular targets for cancer therapy. The objective of this study was to evaluate the expression status of FGFR2 and HER2 in patients with gastric cancer (GC) or colorectal cancer (CRC). METHODS: Archived tumor tissue samples from patients with histologically-confirmed GC or CRC suitable for chemotherapy were analyzed for FGFR2 and HER2 expression using immunohistochemistry and fluorescence in situ hybridization (HER2 in CRC only). RESULTS: A total of 176 GC patients and 389 CRC patients were enrolled. Among patients with GC, 25.6% were FGFR2-positive and 26.1% were HER2-positive. Among patients with CRC, 2.9% were FGFR2-positive and 16.2% were HER2-positive. No clear relationship was found between FGFR2 and HER2 status in either GC or CRC. In GC, FGFR2 and HER2 statuses did not differ between different primary cancer locations, whereas there were some differences between histological types. Based on FGFR2- and/or HER2-positive status, 117 patients were identified as potentially suitable for inclusion in clinical trials of therapeutic agents targeting the relevant protein (GC = 45, CRC = 72; FGFR = 56, HER2 = 62), of whom 7 were eventually enrolled into such clinical trials. CONCLUSIONS: This study indicated the prevalence of FGFR2 and HER2 in GC and CRC in the Japanese population. The screening performed in this study could be useful for identifying eligible patients for future clinical trials of agents targeting these proteins. TRIAL REGISTRATION: Clinical trial registration Japic CTI No.: JapicCTI-163380. https://www. CLINICALTRIALS: jp/cti-user/trial/ShowDirect.jsp?directLink=RNlzx1PPCuT.PrVNPxPRwA .

50Amplification of FGFR2 Gene in Patients with Advanced Gastric Cancer Receiving Chemotherapy: Prevalence and Prognostic Significance.PubMed

Hirokazu Shoji, Yasuhide Yamada, Natsuko Okita, et al.
Anticancer Res. 2015 Sep;35(9):5055-61.
BACKGROUND: Fibroblast growth factors and their receptors regulate key cellular functions, such as proliferation, differentiation and survival. Herein, we studied the prevalence and prognostic role of fibroblast growth factor receptor 2 (FGFR2) amplification in patients with advanced gastric cancer (AGC) who received systemic chemotherapy. PATIENTS AND METHODS: The gene copy number of FGFR2 was investigated in 80 patients with AGC who received systemic chemotherapy. FGFR2 gene status was assessed by dual-color fluorescence in-situ hybridization. RESULTS: Among 80 patients, FGFR2 amplification was observed in seven cases (11.5%). Patients with FGFR2 amplification had significantly shorter overall survival (OS) than did those without FGFR2 amplification (9.1 vs. 16.5 months; p=0.037). In multivariate analysis, disease status and number of metastatic sites were associated with worse OS (p=0.015 and p=0.009, respectively). FGFR2 amplification tended to be correlated with a poorer outcome (p=0.080). CONCLUSION: FGFR2 amplification tended to result in a shorter survival period compared to cases without amplification.

51FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study.PubMed

X Su, P Zhan, P R Gavine, et al.
Br J Cancer. 2014 Feb 18;110(4):967-75. doi: 10.1038/bjc.2013.802. Epub 2014 Jan 23.
BACKGROUND: In preclinical gastric cancer (GC) models, FGFR2 amplification was associated with increased tumour cell proliferation and survival, and drugs targeting this pathway are now in clinical trials. METHODS: FGFR2 FISH was performed on 961 GCs from the United Kingdom, China and Korea, and the relationship with clinicopathological data and overlap with HER2 amplification were analysed. RESULTS: The prevalence of FGFR2 amplification was similar between the three cohorts (UK 7.4%, China 4.6% and Korea 4.2%), and intratumoral heterogeneity was observed in 24% of FGFR2 amplified cases. FGFR2 amplification was associated with lymph node metastases (P<0.0001). FGFR2 amplification and polysomy were associated with poor overall survival (OS) in the Korean (OS: 1.83 vs 6.17 years, P=0.0073) and UK (OS: 0.45 vs 1.9 years, P<0.0001) cohorts, and FGFR2 amplification was an independent marker of poor survival in the UK cohort (P=0.0002). Co-amplification of FGFR2 and HER2 was rare, and when high-level amplifications did co-occur these were detected in distinct areas of the tumour. CONCLUSION: A similar incidence of FGFR2 amplification was found in Asian and UK GCs and was associated with lymphatic invasion and poor prognosis. This study also shows that HER2 and FGFR2 amplifications are mostly exclusive.

52Cost-Effectiveness Analysis of Biomarker-Guided Treatment for Metastatic Gastric Cancer in the Second-Line Setting.PubMed

Brianna Lauren, Sassan Ostvar, Elisabeth Silver, et al.
J Oncol. 2020 Feb 17;2020:2198960. doi: 10.1155/2020/2198960. eCollection 2020.
BACKGROUND: The 5-year survival rate of patients with metastatic gastric cancer (GC) is only 5%. However, trials have demonstrated promising antitumor activity for targeted therapies/immunotherapies among chemorefractory metastatic GC patients. Pembrolizumab has shown particular efficacy among patients with programmed death ligand-1 (PD-L1) expression and high microsatellite instability (MSI-H). The aim of this study was to assess the effectiveness and cost-effectiveness of biomarker-guided second-line GC treatment. METHODS: We constructed a Markov decision-analytic model using clinical trial data. Our model compared pembrolizumab monotherapy and ramucirumab/paclitaxel combination therapy for all patients and pembrolizumab for patients based on MSI status or PD-L1 expression. Paclitaxel monotherapy and best supportive care for all patients were additional comparators. Costs of drugs, treatment administration, follow-up, and management of adverse events were estimated from a US payer perspective. The primary outcomes were quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay threshold of $100,000/QALY over 60 months. Secondary outcomes were unadjusted life years (survival) and costs. Deterministic and probabilistic sensitivity analyses were performed to evaluate model uncertainty. RESULTS: The most effective strategy was pembrolizumab for MSI-H patients and ramucirumab/paclitaxel for all other patients, adding 3.8 months or 2.0 quality-adjusted months compared to paclitaxel. However, this strategy resulted in a prohibitively high ICER of $1,074,620/QALY. The only cost-effective strategy was paclitaxel monotherapy for all patients, with an ICER of $53,705/QALY. CONCLUSION: Biomarker-based treatments with targeted therapies/immunotherapies for second-line metastatic GC patients substantially improve unadjusted and quality-adjusted survival but are not cost-effective at current drug prices.

53Access to anti-cancer drugs in India: is there a need to revise reimbursement policies?PubMed

Gertruud Haitsma, Himanshu Patel, Parthasarathi Gurumurthy, et al.
Expert Rev Pharmacoecon Outcomes Res. 2018 Jun;18(3):289-296. doi: 10.1080/14737167.2018.1444479. Epub 2018 Feb 26.
BACKGROUND: The aim of this study was to examine the access of Indian cancer patients to optimum cancer care under selected government schemes by reviewing reimbursement schemes for cancer care in India. METHODS: All cancer care reimbursement schemes in India were identified and three highly utilized schemes (VAS, RAS, CMCHS) were selected. Quality of breast, colorectal, lung, head & neck, and gastric cancer care was reviewed with respect to NCCN guidelines. Direct medical costs and shortage of budget in reimbursed amounts were calculated for each listed chemotherapy regimen. RESULTS: Medical oncology practice following the schemes' formularies is inferior to recommendations by the NCCN guidelines. Innovative treatment (targeted therapies) like trastuzumab, pertuzumab (breast), bevacizumab, cetuximab, panitumumab (colorectal), erlotinib, gefitinib, crizotinib, and nivolumab (lung) are either not reimbursed (VAS, CMCHS) or partially reimbursed (RAS). Average shortage of budget was found to be 43% (breast), 55% (colorectal), 74% (lung), 7% (head & neck), and 51% (gastric cancer). CONCLUSIONS: Policy makers should consider addition of newer treatments, exclusion of sub-optimal treatments, increments in per patient budget and optimization of supportive care, which may contribute to improvements in survival and quality of life for Indian cancer patients.