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

• DOI: 10.1038/ng.3990
• Publication Date: 2017-11-06T16:03:22Z
• Authors: 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 Giannikopo...; Andrew D Simmons; Philip C Mack; David R Gandara; Hatim Husain; Robert C Doebele; Jonathan W Riess; Maximilian Diehn; Charles Swanton; Trever G Bivona
• Keywords: Lung Neoplasms; Class I Phosphatidylinositol 3-Kinases; Agricultural Biotechnology; Agricultural biotechnology; Bioinformatics and Computational Biology; 610; Veterinary and Food Sciences; Kaplan-Meier Estimate; Medical and Health Sciences; Article; Cell Line; Clonal Evolution; 03 medical and health sciences; 0302 clinical medicine; Clinical Research; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Genetics; Humans; Non-Small-Cell Lung; Lung; Protein Kinase Inhibitors; Wnt Signaling Pathway; beta Catenin; Cancer; Cell Proliferation; Neoplasm Staging; Agricultural; Neoplastic; Tumor; Lung Cancer; Carcinoma; Biological Sciences; Bioinformatics and computational biology; Cyclin-Dependent Kinases; 4.1 Discovery and preclinical testing of markers and technologies; 3. Good health; ErbB Receptors; Gene Expression Regulation, Neoplastic; Gene Expression Regulation; Mutation; Women's Health; Developmental Biology

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.