Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLC

SummaryMET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers and causes resistance to EGFR kinase inhibitors. We demonstrate that MET activation by its ligand, HGF, also induces drug resistance, but through GAB1 signaling. Using high-throughput FISH analyses in both cell lines and in patients with lung cancer, we identify subpopulations of cells with MET amplification prior to drug exposure. Surprisingly, HGF accelerates the development of MET amplification both in vitro and in vivo. EGFR kinase inhibitor resistance, due to either MET amplification or autocrine HGF production, was cured in vivo by combined EGFR and MET inhibition. These findings highlight the potential to prospectively identify treatment naive, patients with EGFR-mutant lung cancer who will benefit from initial combination therapy.

► Rare MET-amplified cells exist in some EGFR-mutant lung cancers before treatment
► HGF induces resistance to tyrosine kinase inhibitors in EGFR-addicted cancers
► HGF accelerates MET amplification by expanding preexisting MET-amplified cells
► Analysis of pretreatment cancers identifies those poised to become MET amplified