PDF(Pubmed)
Abstract：
Recently approved and highly specific small-molecule inhibitors of c-MET exon 14 skipping mutations (e.g., capmatinib, tepotinib) are a new and important therapeutic option for the treatment of non-small cell lung cancer (NSCLC) patients harbouring c-MET alterations. Several experimental studies have provided compelling evidence that c-MET is involved in the regulation of the immune response by up-regulating inhibitory molecules (e.g., PD-L1) and down-regulating of immune stimulators (e.g., CD137, CD252, CD70, etc.). In addition, c-MET was found to be implicated in the regulation of the inflamed tumour microenvironment (TME) and thereby contributing to an increased immune escape of tumour cells from T cell killing. Moreover, it is a major resistance mechanism following treatment of epidermal growth factor receptor mutations (EGFRmut) with tyrosine kinase receptor inhibitors (TKIs). In line with these findings c-MET alterations have also been shown to be associated with a worse clinical outcome and a poorer prognosis in NSCLC patients. However, the underlying mechanisms for these experimental observations are neither fully evaluated nor conclusive, but clearly multifactorial and most likely tumour-specific. In this regard the clinical efficacy of checkpoint inhibitors (CPIs) and TKIs against EGFRmut in NSCLC patients harbouring c-MET alterations is also not yet established, and further research will certainly provide some guidance as to optimally utilise CPIs and c-MET inhibitors in the future.
摘要：
最近批准的c-MET外显子14跳跃突变的高特异性小分子抑制剂（例如，卡马替尼,tepotinib）是治疗c-MET改变的非小细胞肺癌（NSCLC）患者的一种新的重要治疗选择。几项实验研究提供了令人信服的证据，表明c-MET通过上调抑制分子参与免疫反应的调节（例如，PD-L1)和下调免疫刺激因子(例如，CD137、CD252、CD70等。).此外,发现c-MET与发炎的肿瘤微环境（TME）的调节有关，从而有助于增加肿瘤细胞对T细胞杀伤的免疫逃逸。此外，它是用酪氨酸激酶受体抑制剂（TKIs）治疗表皮生长因子受体突变（EGFRmut）后的主要耐药机制。与这些发现一致，c-MET改变也被证明与NSCLC患者更差的临床结果和更差的预后相关。然而,这些实验观察的潜在机制既没有得到充分评估也没有结论，但显然是多因素的，最有可能是肿瘤特异性的。在这方面，检查点抑制剂（CPIs）和TKIs对携带c-MET改变的NSCLC患者的EGFRmut的临床疗效尚未确定。进一步的研究肯定会为将来最佳利用CPIs和c-MET抑制剂提供一些指导。
