Structural Alterations of MET Trigger Response to MET Kinase Inhibition in Lung Adenocarcinoma Patients.

Abstract

<b>Purpose:</b> We sought to investigate the clinical response to MET inhibition in patients diagnosed with structural MET alterations and to characterize their functional relevance in cellular models.<b>Experimental Design:</b> Patients were selected for treatment with crizotinib upon results of hybrid capture-based next-generation sequencing. To confirm the clinical observations, we analyzed cellular models that express these MET kinase alterations.<b>Results:</b> Three individual patients were identified to harbor alterations within the MET receptor. Two patients showed genomic rearrangements, leading to a gene fusion of <i>KIF5B</i> or <i>STARD3NL</i> and <i>MET</i> One patient diagnosed with an EML4-ALK rearrangement developed a MET kinase domain duplication as a resistance mechanism to ceritinib. All 3 patients showed a partial response to crizotinib that effectively inhibits MET and ALK among other kinases. The results were further confirmed using orthogonal cellular models.<b>Conclusions:</b> Crizotinib leads to a clinical response in patients with MET rearrangements. Our functional analyses together with the clinical data suggest that these structural alterations may represent actionable targets in lung cancer patients. <i>Clin Cancer Res; 24(6); 1337-43. ©2017 AACR</i>.