MET Amplification as a Resistance Driver to TKI Therapies in Lung Cancer: Clinical Challenges and Opportunities

Abstract

Targeted therapy has emerged as an important pillar for the standard of care in oncogene-driven non-small cell lung cancer (NSCLC), which significantly improved outcomes of patients whose tumors harbor oncogenic driver mutations. However, tumors eventually develop resistance to targeted drugs, and mechanisms of resistance can be diverse. MET amplification has been proven to be a driver of resistance to tyrosine kinase inhibitor (TKI)-treated advanced NSCLC with its activation of EGFR, ALK, RET, and ROS-1 alterations. The combined therapy of MET-TKIs and EGFR-TKIs has shown outstanding clinical efficacy in EGFR-mutated NSCLC with secondary MET amplification-mediated resistance in a series of clinical trials. In this review, we aimed to clarify the underlying mechanisms of MET amplification-mediated resistance to tyrosine kinase inhibitors, discuss the ways and challenges in the detection and diagnosis of MET amplifications in patients with metastatic NSCLC, and summarize the recently published clinical data as well as ongoing trials of new combination strategies to overcome MET amplification-mediated TKI resistance.