文章：

非小细胞肺癌中的MET：穿越“漫长曲折之路”寻找靶点

MET in Non-Small-Cell Lung Cancer (NSCLC): Cross ‘a Long and Winding Road’ Looking for a Target

原文发布日期：28 September 2023

DOI: 10.3390/cancers15194779

类型: Article

开放获取: 是

英文摘要：

Non-Small-Cell Lung Cancer (NSCLC) can harbour different MET alterations, such as MET overexpression (MET OE), MET gene amplification (MET AMP), or MET gene mutations. Retrospective studies of surgical series of patients with MET-dysregulated NSCLC have shown worse clinical outcomes irrespective of the type of specific MET gene alteration. On the other hand, earlier attempts failed to identify the ‘druggable’ molecular gene driver until the discovery of MET exon 14 skipping mutations (METex14). METex14 are rare and amount to around 3% of all NSCLCs. Patients with METex14 NSCLC attain modest results when they are treated with immune checkpoint inhibitors (ICIs). New selective MET inhibitors (MET-Is) showed a long-lasting clinical benefit in patients with METex14 NSCLC and modest activity in patients with MET AMP NSCLC. Ongoing clinical trials are investigating new small molecule tyrosine kinase inhibitors, bispecific antibodies, or antibodies drug conjugate (ADCs). This review focuses on the prognostic role of MET, the summary of pivotal clinical trials of selective MET-Is with a focus on resistance mechanisms. The last section is addressed to future developments and challenges.

摘要翻译： 

非小细胞肺癌（NSCLC）可携带多种MET基因异常，包括MET过表达（MET OE）、MET基因扩增（MET AMP）或MET基因突变。针对MET异常NSCLC患者手术标本的回顾性研究表明，无论具体MET基因异常类型如何，患者临床结局均较差。另一方面，在发现MET外显子14跳跃突变（METex14）之前，早期研究未能明确可靶向治疗的分子驱动基因。METex14突变较为罕见，约占所有NSCLC病例的3%。携带METex14突变的NSCLC患者接受免疫检查点抑制剂（ICIs）治疗仅能获得有限疗效。新型选择性MET抑制剂（MET-Is）在METex14 NSCLC患者中展现出持久的临床获益，而在MET AMP NSCLC患者中疗效相对有限。目前正在进行的临床试验正在研究新型小分子酪氨酸激酶抑制剂、双特异性抗体及抗体药物偶联物（ADCs）。本综述重点探讨MET的预后意义，总结选择性MET-Is的关键临床试验并聚焦其耐药机制，最后部分将展望未来发展方向与挑战。

原文链接：

MET in Non-Small-Cell Lung Cancer (NSCLC): Cross ‘a Long and Winding Road’ Looking for a Target