RT Journal Article SR Electronic T1 Co-occurring genetic alterations in the RAS pathway promote resistance to MET inhibitor treatment in non-small cell lung cancer with a MET exon 14 skipping mutation JF bioRxiv FD Cold Spring Harbor Laboratory SP 374181 DO 10.1101/374181 A1 Julia K. Rotow A1 Philippe Gui A1 Wei Wu A1 Victoria M. Raymond A1 Richard B. Lanman A1 Frederic J. Kaye A1 Nir Peled A1 Ferran Fece de la Cruz A1 Brandon Nadres A1 Ryan B. Corcoran A1 Iwei Yeh A1 Boris C. Bastian A1 Petr Starostik A1 Kimberly Newsom A1 Victor R Olivas A1 Alexander M. Wolff A1 James S. Fraser A1 Eric A. Collisson A1 Caroline E. McCoach A1 Collin M. Blakely A1 Trever G. Bivona YR 2018 UL http://biorxiv.org/content/early/2018/07/22/374181.abstract AB While patients with advanced-stage non-small cell lung cancers (NSCLCs) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, their long-term survival is limited by drug resistance. The molecular basis for this resistance remains incompletely understood. Through targeted sequencing analysis of cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14 NSCLC, we find prominent co-occurring RAS pathway gene alterations (e.g. in KRAS/NRAS, NF1). Clinical resistance to MET TKI treatment was associated with the presence of these co-occurring alterations. In a new preclinical model expressing a METex14 mutation, KRAS overexpression promoted MET TKI resistance, which was overcome by co-treatment with crizotinib and the MEK inhibitor trametinib. Our study provides a genetic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy to enhance clinical outcomes.Statement of Significance This report describes targeted sequencing of the largest reported cohort of advanced-stage NSCLC with a MET exon 14 skipping mutation. The data uncover certain RAS pathway genetic alterations as potential mediators of MEK TKI resistance, which could be overcome by MEK and MET co-inhibition in NSCLC.