Ooki Akira, Yamaguchi Kensei
Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
Gastric Cancer. 2021 Nov;24(6):1169-1183. doi: 10.1007/s10120-021-01235-z. Epub 2021 Aug 16.
Despite recent advances in the systemic treatment of metastatic gastric cancer (GC), prognostic outcomes remain poor. Considerable research effort has been invested in characterizing the genomic landscape of GC and identifying potential therapeutic targets. FGFR2 is one of the most attractive targets because aberrations in this gene are frequently associated with GC, particularly the diffuse type in Lauren's classification, which confers an unfavorable prognosis. Based on the preclinical data, the FGFR2 signaling pathway plays a key role in the development and progression of GC, and several FGFR inhibitors have been clinically assessed. However, the lack of robust treatment efficacy has hampered precision medicine for patients with FGFR2-aberrant GC. Recently, the clinical benefits of the FGFR2-IIIb-selective monoclonal antibody bemarituzumab for FGFR2b-positive GC patients were shown in a randomized phase II FIGHT trial of bemarituzumab combined with the first-line chemotherapy. This trial demonstrates proof of concept, suggesting that FGFR2 is a relevant therapeutic target for patients with FGFR2b-positive GC and that bemarituzumab brings new hope for diffuse-type GC patients. In this review, we summarize the oncogenic roles of FGFR2 signaling and highlight the most recent advances in FGFR inhibitors based on the findings of pivotal clinical trials for patients with FGFR2-aberrant GC. Thus, the era of precision medicine for patients with FGFR2-aberrant GC will be opened.
尽管转移性胃癌（GC）的系统治疗最近取得了进展，但其预后结果仍然很差。在表征GC的基因组图谱和识别潜在治疗靶点方面已经投入了大量的研究工作。FGFR2是最具吸引力的靶点之一，因为该基因的畸变经常与GC相关，特别是劳伦分类中的弥漫型，其预后不良。基于临床前数据，FGFR2信号通路在GC的发生和发展中起关键作用，并且几种FGFR抑制剂已经进行了临床评估。然而，缺乏强大的治疗效果阻碍了FGFR2异常GC患者的精准医学发展。最近，在一项关于bemarituzumab联合一线化疗的随机II期FIGHT试验中，显示了FGFR2-IIIb选择性单克隆抗体bemarituzumab对FGFR2b阳性GC患者的临床益处。该试验证明了概念验证，表明FGFR2是FGFR2b阳性GC患者的相关治疗靶点，并且bemarituzumab为弥漫型GC患者带来了新的希望。在这篇综述中，我们总结了FGFR2信号传导的致癌作用，并根据FGFR2异常GC患者关键临床试验的结果强调了FGFR抑制剂的最新进展。因此，FGFR2异常GC患者的精准医学时代即将开启。
