The mesenchymal–epithelial transition (MET) receptor is a tyrosine kinase activated by its sole known ligand, hepatocyte growth factor (HGF). MET signaling regulates key cellular processes, including proliferation, survival, migration, motility, and angiogenesis. Dysregulation and hyperactivation of this pathway are implicated in multiple malignancies, including lung, breast, colorectal, and gastrointestinal cancers. In non–small cell lung cancer (NSCLC), aberrant activation of theMETproto-oncogene contributes to 1% of known oncogenic drivers and is associated with poor clinical outcomes. Several mechanisms can induce MET hyperactivation, includingMETgene amplification, transcriptional upregulation ofMETorHGF,METfusion genes, andMETexon 14 skipping mutations. Furthermore, MET pathway activation represents a frequent mechanism of acquired resistance to EGFR- and ALK-targeted tyrosine kinase inhibitors (TKIs) in EGFR- and ALK-driven NSCLCs. Although MET has long been recognized as a promising therapeutic target in NSCLC, the clinical efficacy of MET-targeted therapies has historically lagged behind that of EGFR and ALK inhibitors. Encouragingly, several MET TKIs such as capmatinib, tepotinib, and savolitinib have been approved for the treatment ofMETexon 14 skipping mutations. They have also demonstrated potential in overcoming MET-driven resistance to EGFR TKIs or ALK TKIs. On 14 May 2025, the U.S. Food and Drug Administration granted accelerated approval to telisotuzumab vedotin-tllv for adult patients with locally advanced or metastatic non-squamous NSCLC whose tumors exhibit high c-Met protein overexpression and who have already received prior systemic therapy. In this review, we summarize the structure and physiological role of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its contribution to acquired resistance against targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC.
间质-上皮转化（MET）受体是一种酪氨酸激酶，由其唯一已知配体肝细胞生长因子（HGF）激活。MET信号通路调控细胞增殖、存活、迁移、运动及血管生成等关键生物学过程。该通路的异常调控与过度激活与多种恶性肿瘤相关，包括肺癌、乳腺癌、结直肠癌及胃肠道癌症。在非小细胞肺癌（NSCLC）中，MET原癌基因的异常激活约占已知致癌驱动因素的1%，并与不良临床预后相关。MET过度激活可由多种机制诱导，包括MET基因扩增、MET或HGF转录上调、MET融合基因以及MET外显子14跳跃突变。此外，在EGFR或ALK驱动的NSCLC中，MET通路激活常作为对EGFR或ALK靶向酪氨酸激酶抑制剂（TKIs）产生获得性耐药的重要机制。尽管MET长期被视为NSCLC中具有潜力的治疗靶点，但MET靶向治疗的临床疗效历来落后于EGFR和ALK抑制剂。值得鼓舞的是，capmatinib、tepotinib、savolitinib等多种MET-TKIs已获批用于治疗MET外显子14跳跃突变，并显示出克服EGFR-TKIs或ALK-TKIs的MET驱动耐药的潜力。2025年5月14日，美国食品药品监督管理局加速批准替利索妥珠单抗维多汀-tllv用于治疗肿瘤呈现高水平c-Met蛋白过表达、且既往接受过全身治疗的局部晚期或转移性非鳞状NSCLC成人患者。本文综述了MET受体的结构及生理功能、MET异常激活的分子机制、其在靶向治疗获得性耐药中的作用，以及NSCLC中靶向MET改变的新兴策略。
肿瘤(癌症)患者之家