期刊
NATURE GENETICS
卷 49, 期 12, 页码 1693-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3990
关键词
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资金
- NIH [NCI-R01CA169338, NCI-DP2CA174497]
- Pew Charitable Trust
- Stewart Foundation
- Searle Foundation
- AACR
- Lung Cancer Research Foundation
- Cancer Research UK [19310, 20466, 17786] Funding Source: researchfish
- Medical Research Council [MR/P014712/1] Funding Source: researchfish
- Rosetrees Trust [M391, M231-CD1, M445, M179, M640] Funding Source: researchfish
- The Francis Crick Institute [10485, 10172, 10359, 10467, C28575/A25223, C60895/A23896, 10170, 10169, 10174, VEG 108844, A1278] Funding Source: researchfish
- MRC [MR/P014712/1] Funding Source: UKRI
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/beta-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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