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.
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The authors acknowledge funding support from the NIH (NCI-R01CA169338, NIH Director's New Innovator Award NCI-DP2CA174497), the Pew Charitable Trust, Stewart Foundation, and Searle Foundation (to T.G.B.), and the AACR and Lung Cancer Research Foundation (C.M.B.). The authors thank J. Blakely for artwork and A. Sabnis, R. Okimoto, A. Tulpule, and M. Hutchinson for critical review and input on the manuscript. The authors acknowledge the following researchers for providing plasmids through Addgene: E. Campeau (University of Massachusetts Medical School); H. Land and J. Morgenstern (Imperial Cancer Research Fund); B. Weinberg (Whitehead Institute for Biomedical Research); J. Zhao (Dana-Farber Cancer Institute, Harvard Medical School); and E. Fearon (University of Michigan School of Medicine).
Integrated supplementary information
cfDNA alterations in EGFR-mutant positive lung cancer patientsSomatic variants, copy number gains and clonality of alterations detected in cfDNA of EGFR-mutant positive patients.
cfDNA alterations in EGFR-mutant negative lung cancer patientsSomatic variants, copy number gains and clonality of alterations detected in cfDNA of EGFR-mutant negative patients.
Demographic information and genomic alterations identified in cfDNA of EGFR-mutant lung cancer patients.Age, gender, smoking history, prior treatment and treatment outcomes for 137 samples from 97 patients with known clinical course.
Demographic information, clinical response data, and genomic alterations identified in cfDNA of patients treated with an EGFR-TKI.Age, gender, smoking history, prior treatment and treatment outcomes for 73 patients treated with an EGFR TKI including 41 patients treated with osimertinib.
Somatic mutations and clonality analysis of tumor samples described in Figure 5.Somatic variants identified in 7 tumor samples from patient with EGFR-mutant lung cancer throughout the course of her disease with clonality assessment for each variant determined by PyClone.
Copy number alterations in tumor samples described in Figure 5 and Supplementary Figure 7.Chromosomal regions of copy number gain and loss identified in in 7 tumor samples from patient with EGFR-mutant lung cancer throughout the course of her disease.