Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment in MET exon 14 skipping mutation positive lung cancer
Julia K Rotow,
Victoria M Raymond,
Richard B Lanman,
Frederic J Kaye,
Ferran Fece de la Cruz,
Ryan B Corcoran,
Boris C. Bastian,
Victor R Olivas,
Alexander M Wolff,
James S Fraser,
Caroline E McCoach,
D Ross Camidge,
Trever G. Bivona,
Collin M. Blakely
Posted 22 Jul 2018
bioRxiv DOI: 10.1101/374181 (published DOI: 10.1158/1078-0432.CCR-19-1667)
Posted 22 Jul 2018
PURPOSE While patients with advanced-stage non-small cell lung cancers (NSCLCs) harboring MET exon 14 skipping mutations ( METex 14) 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. METHODS Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex 14-mutated NSCLC. RESULTS Prominent co-occurring RAS-MAPK pathway gene alterations (e.g. in KRAS, NF1 ) were detected in NSCLCs with METex 14 skipping alterations as compared to 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 METex 14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by co-treatment with crizotinib and the MEK inhibitor trametinib. CONCLUSION Our study provides a genomic landscape of co-occurring alterations in advanced-stage METex 14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.
- Downloaded 1,369 times
- Download rankings, all-time:
- Site-wide: 15,102
- In cancer biology: 327
- Year to date:
- Site-wide: 35,127
- Since beginning of last month:
- Site-wide: 48,031
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!