University of California, San Francisco, San Francisco, CA
Julia Rotow , Wei Wu , Collin M. Blakely , Richard B. Lanman , Victoria M. Raymond , Frederic J. Kaye , Phillipe Gui , James Fraser , Alexander Wolff , Eric Andrew Collisson , Caroline Elizabeth McCoach , Trever Grant Bivona
Background: METex14 oncogenic driver mutations are present in 2-4% of lung adenocarcinoma. While second-site MET mutations have been reported at MET TKI resistance, the factors influencing response to MET TKI therapy are not yet fully characterized. The landscape of co-occurring genetic alterations, which correlates with treatment response in EGFR-mutant NSCLC, is incompletely understood in METex14 NSCLC. Methods: Targeted exome sequencing of cell-free DNA (cfDNA) obtained via the clinical Guardant360 assay for co-occurring alterations (somatic variants, copy-number alterations) in 68 cancer-associated genes within 70 samples from 65 patients with advanced stage METex14 NSCLC. Synonymous mutations and those with predicted neutral or unknown functional impact were excluded. Results: 81.4% of METex14-positive samples contained concurrent genomic alterations, with a mean of an additional 2.6 (range 0-20) alterations/sample. Mutations or amplifications in TP53 (44.6% of patients), CDK4 (13.8%), EGFR (12.3%), and NF1 (12.3%) were most common. Pathway analysis identified receptor tyrosine kinases (40%), cell cycle mediators (29.2%), and the MAPK pathway (26.2%) as frequently altered. Alterations in the MAPK pathway have not yet been implicated in TKI resistance in METex14 NSCLC. We identified two patients with newly acquired MAPK pathway alterations (KRAS amplification, KRAS G12D mutation) at MET TKI resistance. Conclusions: The cfDNA from patients with METex14 NSCLC frequently contains additional oncogenic co-alterations. Among downstream MET signaling mediators there is a high rate of concurrent MAPK pathway alterations in METex14 NSCLC, as well as newly acquired MAPK pathway alterations at resistance to MET TKI therapy. The MAPK pathway is a potential therapeutic target to enhance treatment responses in METex14 NSCLC.
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Abstract Disclosures
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