Dataset Information

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

ABSTRACT: PURPOSE:Although patients with advanced-stage non-small cell lung cancers (NSCLC) harboring MET exon 14 skipping mutations (METex14) 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. EXPERIMENTAL DESIGN:Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14-mutated NSCLC. RESULTS:Prominent co-occurring RAS-MAPK pathway gene alterations (e.g., in KRAS, NF1) were detected in NSCLCs with METex14 skipping alterations as compared with EGFR-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 METex14 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. CONCLUSIONS:Our study provides a genomic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.

SUBMITTER: Rotow JK

PROVIDER: S-EPMC6980768 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Rotow Julia K JK Gui Philippe P Wu Wei W Raymond Victoria M VM Lanman Richard B RB Kaye Frederic J FJ Peled Nir N Fece de la Cruz Ferran F Nadres Brandon B Corcoran Ryan B RB Yeh Iwei I Bastian Boris C BC Starostik Petr P Newsom Kimberly K Olivas Victor R VR Wolff Alexander M AM Fraser James S JS Collisson Eric A EA McCoach Caroline E CE Camidge D Ross DR Pacheco Jose J Bazhenova Lyudmila L Li Tianhong T Bivona Trever G TG Blakely Collin M CM

Clinical cancer research : an official journal of the American Association for Cancer Research 20190923 2

<h4>Purpose</h4>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.<h4>Experimental design</h4>Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with ...[more]

PMID: 31548343

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Project description:IntroductionGenomic alterations in the juxtamembrane exon 14 splice sites in NSCLC lead to increased MET stability and oncogenesis. We present the largest cohort study of MET Exon 14 (METex14) using whole transcriptome sequencing.MethodsA total of 21,582 NSCLC tumor samples underwent complete genomic profiling with next-generation sequencing of DNA (592 Gene Panel, NextSeq, whole exome sequencing, NovaSeq) and RNA (NovaSeq, whole transcriptome sequencing). Clinicopathologic information including programmed death-ligand 1 and tumor mutational burden were collected and RNA expression for mutation subtypes and MET amplification were quantified. Immunogenic signatures and potential pathways of invasion were characterized using single-sample gene set enrichment analysis and mRNA gene signatures.ResultsA total of 533tumors (2.47%) with METex14 were identified. The most common alterations were point mutations (49.5%) at donor splice sites. Most alterations translated to increased MET expression, with MET co-amplification resulting in synergistic increase in expression (q < 0.05). Common coalterations were amplifications of MDM2 (19.0% versus 1.8% wild-type [WT]), HMGA2 (13.2% versus 0.98% WT), and CDK4 (10.0% versus 1.5% WT) (q < 0.05). High programmed death-ligand 1 > 50% (52.5% versus 27.3% WT, q < 0.0001) and lower proportion of high tumor mutational burden (>10 mutations per megabase, 8.3% versus 36.7% WT, p < 0.0001) were associated with METex14, which were also enriched in both immunogenic signatures and immunosuppressive checkpoints. Pathways associated with METex14 included angiogenesis and apical junction pathways (q < 0.05).ConclusionsMETex14 splicing alterations and MET co-amplification translated to higher and synergistic MET expression at the transcriptomic level. High frequencies of MDM2 and CDK4 co-amplifications and association with multiple immunosuppressive checkpoints and angiogenic pathways provide insight into potential actionable targets for combination strategies in METex14 NSCLC.

Dataset Information

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

Publications

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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