Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers

Collin M. Blakely, Thomas B.K. Watkins, Wei Wu, Beatrice Gini, Jacob J. Chabon, Caroline E. McCoach, Nicholas McGranahan, Gareth A. Wilson, Nicolai J. Birkbak, Victor R. Olivas, Julia Rotow, Ashley Maynard, Victoria Wang, Matthew A. Gubens, Kimberly C. Banks, Richard B. Lanman, Aleah F. Caulin, John St John, Anibal R. Cordero, Petros GiannikopoulosAndrew D. Simmons, Philip Mack, David R Gandara, Hatim Husain, Robert C. Doebele, Jonathan Riess, Maximilian Diehn, Charles Swanton, Trever G. Bivona

Research output: Contribution to journalArticle

136 Scopus citations

Abstract

A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers. We defined new pathways limiting EGFR-inhibitor response, including WNT/β-catenin alterations and cell-cycle-gene (CDK4 and CDK6) mutations. Tumor genomic complexity increases with EGFR-inhibitor treatment, and co-occurring alterations in CTNNB1 and PIK3CA exhibit nonredundant functions that cooperatively promote tumor metastasis or limit EGFR-inhibitor response. This study calls for revisiting the prevailing single-gene driver-oncogene view and links clinical outcomes to co-occurring genetic alterations in patients with advanced-stage EGFR-mutant lung cancer.

Original languageEnglish (US)
Pages (from-to)1693-1704
Number of pages12
JournalNature Genetics
Volume49
Issue number12
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • Genetics

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    Blakely, C. M., Watkins, T. B. K., Wu, W., Gini, B., Chabon, J. J., McCoach, C. E., McGranahan, N., Wilson, G. A., Birkbak, N. J., Olivas, V. R., Rotow, J., Maynard, A., Wang, V., Gubens, M. A., Banks, K. C., Lanman, R. B., Caulin, A. F., St John, J., Cordero, A. R., ... Bivona, T. G. (2017). Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nature Genetics, 49(12), 1693-1704. https://doi.org/10.1038/ng.3990