학술논문
Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers
Document Type
article
Author
Blakely, Collin M; Watkins, Thomas BK; Wu, Wei; Gini, Beatrice; Chabon, Jacob J; McCoach, Caroline E; McGranahan, Nicholas; Wilson, Gareth A; Birkbak, Nicolai J; Olivas, Victor R; Rotow, Julia; Maynard, Ashley; Wang, Victoria; Gubens, Matthew A; Banks, Kimberly C; Lanman, Richard B; Caulin, Aleah F; St John, John; Cordero, Anibal R; Giannikopoulos, Petros; Simmons, Andrew D; Mack, Philip C; Gandara, David R; Husain, Hatim; Doebele, Robert C; Riess, Jonathan W; Diehn, Maximilian; Swanton, Charles; Bivona, Trever G
Source
Nature Genetics. 49(12)
Subject
Language
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.