The hepatocyte growth factor receptor (MET) is a receptor tyrosine kinase (RTK) that mediates the activity of a variety of downstream pathways upon its activation. These pathways regulate various physiological processes within the cell, including growth, survival, proliferation, and motility. Under normal physiological conditions, this allows MET to regulate various development and regenerative processes; however, mutations resulting in aberrant MET activity and the consequent dysregulation of downstream signaling can contribute to cellular pathophysiology. Mutations within MET have been identified in a variety of cancers and have been shown to mediate tumorigenesis by increasing RTK activity and downstream signaling. In lung cancer specifically, a number of patients have been identified as possessing MET alterations, commonly receptor amplification (METamp) or splice site mutations resulting in loss of exon 14 (METex14). Due to MET’s role in mediating oncogenesis, it has become an attractive clinical target and has led to the development of various targeted therapies, including MET tyrosine kinase inhibitors (TKIs). Unfortunately, these TKIs have demonstrated limited clinical efficacy, as patients often present with either primary or acquired resistance to these therapies. Mechanisms of resistance vary but often occur through off-target or bypass mechanisms that render downstream signaling pathways insensitive to MET inhibition. This review provides an overview of the therapeutic landscape for MET-positive cancers and explores the various mechanisms that contribute to therapeutic resistance in these cases.
肝细胞生长因子受体（MET）是一种受体酪氨酸激酶（RTK），其激活后可介导多种下游通路活性。这些通路调控细胞内的多种生理过程，包括生长、存活、增殖和运动。在正常生理条件下，MET通过这一机制参与调控多种发育与再生过程；然而，导致MET异常活化的突变及其引发的下游信号传导失调，可能参与细胞病理生理过程。多种癌症中已发现MET突变，研究证实其可通过增强RTK活性及下游信号传导介导肿瘤发生。尤其在肺癌领域，已发现大量患者存在MET变异，常见类型包括受体扩增（METamp）或导致14号外显子缺失（METex14）的剪接位点突变。鉴于MET在介导肿瘤发生中的关键作用，其已成为极具吸引力的临床靶点，并推动了多种靶向疗法的研发，包括MET酪氨酸激酶抑制剂（TKIs）。然而，这些TKIs的临床疗效有限，患者常出现原发性或获得性耐药。耐药机制多样，但通常通过脱靶或旁路机制实现，使得下游信号通路对MET抑制不再敏感。本综述系统梳理了MET阳性癌症的治疗现状，并深入探讨了导致此类病例治疗耐药的各种机制。
MET Activation in Lung Cancer and Response to Targeted Therapies
肿瘤(癌症)患者之家