Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, 106 Zhongshan Er Rd, Guangzhou 510080, Guangdong, People's Republic of China.
Department of Thoracic Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands.
Cancer Treat Rev. 2021 Apr;95:102173. doi: 10.1016/j.ctrv.2021.102173. Epub 2021 Mar 1.
The mesenchymal-epithelial transition (MET) receptor tyrosine kinase binds the hepatocyte growth factor to activate downstream cell signaling pathways involved in cell proliferation, survival, and migration. Several genetic mechanisms can result in an aberrant activation of this receptor in cancer cells. One such activating mechanism involves the acquisition of gene mutations that cause MET exon 14 skipping (METex14) during mRNA splicing. Mutations leading to METex14 are found in approximately 3-4% of patients with non-small cell lung cancer (NSCLC). Accumulating evidence suggests that METex14 is a true, independent oncogenic driver in NSCLC, as well as being an independent prognostic factor for poorer survival in patients with NSCLC. The successes of target therapies have relied on improved understanding of the genetic alterations that lead to the dysregulation of the molecular pathways and more advanced molecular diagnostics. Multiple efforts have been made to target the MET pathway in cancer; however, real clinical progress has only occurred since the emergence of METex14 as a valid biomarker for MET inhibition. Capmatinib is a highly potent and selective type Ib inhibitor of MET. Following preclinical demonstration of activity against MET-dependent cancer cell line growth and MET-driven tumor growth in xenograft models, data from a phase 1 clinical trial showed an acceptable safety profile of capmatinib and preliminary evidence of efficacy in patients with MET-dysregulated NSCLC. The multicohort GEOMETRY mono-1 phase 2 trial reported objective response rates of 68% and 41% in treatment-naïve and in pre-treated patients with METex14 advanced NSCLC, respectively. These results have supported the approval of capmatinib by the US Food and Drug Administration for patients with metastatic NSCLC harboring METex14.
间质-上皮转化（MET）受体酪氨酸激酶与肝细胞生长因子结合，激活下游细胞信号通路，参与细胞增殖、存活和迁移。几种遗传机制可导致癌细胞中该受体的异常激活。一种激活机制涉及获得基因突变，导致 mRNA 剪接过程中 MET 外显子 14 跳跃（METex14）。导致 METex14 的突变约占非小细胞肺癌（NSCLC）患者的 3-4%。越来越多的证据表明，METex14 是 NSCLC 中的一种真正的、独立的致癌驱动因子，也是 NSCLC 患者生存较差的独立预后因素。靶向治疗的成功依赖于对导致分子通路失调的遗传改变的深入了解，以及更先进的分子诊断。人们已经做出了多种努力来靶向癌症中的 MET 通路；然而，只有在 METex14 作为 MET 抑制的有效生物标志物出现后，才取得了真正的临床进展。卡马替尼是一种高效且选择性的 MET 型 Ib 抑制剂。在临床前证明对依赖 MET 的癌细胞系生长和异种移植模型中 MET 驱动的肿瘤生长具有活性后，来自 1 期临床试验的数据显示卡马替尼具有可接受的安全性特征，并初步证明了在 MET 失调的 NSCLC 患者中的疗效。多队列 GEOMETRY mono-1 期 2 期试验报告，在初治和经治的 METex14 晚期 NSCLC 患者中，客观缓解率分别为 68%和 41%。这些结果支持美国食品和药物管理局批准卡马替尼用于转移性 NSCLC 患者，这些患者携带 METex14。
