Data from Co-occurring Alterations in the RAS–MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer

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<div>AbstractPurpose:<p>Although patients with advanced-stage non–small cell lung cancers (NSCLC) harboring <i>MET</i> exon 14 skipping mutations (<i>MET</i>ex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.</p>Experimental Design:<p>Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage <i>MET</i>ex14-mutated NSCLC.</p>Results:<p>Prominent co-occurring RAS–MAPK pathway gene alterations (e.g., in <i>KRAS, NF1</i>) were detected in NSCLCs with <i>MET</i>ex14 skipping alterations as compared with <i>EGFR</i>-mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS–MAPK pathway co-occurring alterations. In a preclinical model expressing a canonical <i>MET</i>ex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by cotreatment with crizotinib and the MEK inhibitor trametinib.</p>Conclusions:<p>Our study provides a genomic landscape of co-occurring alterations in advanced-stage <i>MET</i>ex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.</p></div>