Acquired <i>MET</i> Y1248H and D1246N Mutations Mediate Resistance to MET Inhibitors in Non–Small Cell Lung Cancer

Abstract

<b>Purpose:</b><i>MET</i> amplification, responsible for 20% of acquired resistance to EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC), presents an attractive target. Numerous studies have conferred susceptibility of <i>MET</i> mutations and focal amplification to targeted MET-TKIs. However, the mechanism underlying MET-TKIs-induced resistance remains elusive.<b>Experimental Design:</b> We conducted a cohort of 12 patients with advanced NSCLC who developed resistance to a combinatorial therapy consisting of gefitinib and a type I MET-TKI. We performed capture-based targeted ultra-deep sequencing on serial tumor biopsies and plasmas ctDNA samples to detect and quantify genetic alterations.<b>Results:</b> We identified 2 newly acquired <i>MET</i> mutations, Y1248H and D1246N, in 2 patients and further confirmed their resistance against type I MET-TKIs <i>in silco, in vitro</i>, and <i>in vivo</i> Interestingly, NIH3T3 cells harboring either mutation exhibited responses to type II MET-TKIs, suggesting sequential use of MET-TKIs may offer a more durable response. In addition, we also discovered that EGFR amplification may act as an alternative MET-TKI resistance mechanism.<b>Conclusions:</b> Our study provides insight into the diversity of mechanisms underlying MET-TKI-induced resistance and highlights the potential of sequential use of MET-TKIs. <i>Clin Cancer Res; 23(16); 4929-37. ©2017 AACR</i>.