The structural and functional basis of MET exon 14 activation and acquired drug resistance

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Project Summary/Abstract Summary: Lung cancer is the largest cancer killer but is also a heterogeneous disease in which different oncoproteins contribute to genetic subtypes, some of which carry specific treatments. Despite favorable outcomes when therapies are matched to driving oncogenes, only small fraction of lung cancer patients are treated in a targeted manner. Our goal is to optimize targeted therapy for the large proportion of lung cancer patients harboring activating mutations in the Mesenchymal Epithelial Transformation (MET) gene. Background: MET mutations are the most recent addition to the list of druggable, recurrently mutated kinases in nonsmall cell lung cancer (NSCLC). We have recently defined the frequency of MET aberrations in NSCLC, and identified exon 14 deletion in the juxtamembrane domain of MET as the most common somatic MET event. The mechanism for its action and its susceptibility to existing targeted MET therapies is however poorly defined, preventing targeted treatment of this large population of NSCLC patients. Methods: We will focus on the signaling and structural effects MET exon 14 mutations impart with the goal of understanding the mechanism of action underlying selection for this mutation in NSCLC. We will first characterize the mechanism by which the juxtamembrane segment of MET regulates the kinase, using purified recombinant MET fragments from its intracellular domain. Next, we will study how exon 14 deletions influence MET inhibitors' binding and whether mutation confers affinity for specific classes of kinase inhibitors. Finally, we will model resistance mutations to first generation (Type I) MET inhibitors in vivo, and suggest strategies to overcome them using targeted approaches with Type II inhibitors and “off-MET” drug targets. Impact: This project focuses on a common and understudied mutation in lung cancer, the most lethal cancer type, by far. Thousands of Americans die each year with MET-mutated lung cancer, and often do so without being considered for targeted therapy against their tumor's genotype. We will clarify the role MET mutation plays in lung cancer and will structurally define how the most common mutations activate this oncoprotein. This project will foster development of therapies targeting MET exon 14 mutations, and optimize approaches to targeting the most common anticipated routes of resistance.