Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers
Open accessAbstract
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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Several distinct patterns of co-mutations are enriched in metastatic disease, likely reflecting acquisition of traits that promote tumor progression and metastatic dissemination.
“In particular, it is critical to distinguish between early-stage, surgically resected tumors and locally advanced or metastatic disease because several distinct patterns of co-mutations are enriched in metastatic disease, likely reflecting acquisition of traits that promote tumor progression and metastatic dissemination72, 73.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [73]
Mutational inactivation of RB1 is a clonal and early genetic event in 9.5%-12.5% of EGFR-mutant LUAD.
“Mutational inactivation of RB1 is a clonal and early genetic event in 9.5%−12.5% of EGFR-mutant LUAD72, 73, 103, 117.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [73]
The overwhelming majority of EGFR-mutant lung tumors harbor one or more co-mutations, even when analysis is limited to pre-defined sets of cancer-relevant genes within established panels.
“Although EGFR –mutant tumors represent the prototypical oncogene-addicted LUAD subgroup that spearheaded adoption of the single-driver model, the overwhelming majority of EGFR-mutant lung tumors harbor one or more co-mutations, even when the analysis is limited to pre-defined sets of cancer-relevant genes within established panels (FoundationOne, Guardant360, MSK-IMPACT)15, 59, 72, 73.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [73]
In vitro, PIK3CA mutations that co-occur enhance invasion and migration of cells.
“In vitro, co-occurring PIK3CA mutations promote cellular invasion and migration”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [73]
Some in vivo studies link co-occurring PIK3CA mutations to poorer overall survival.
“in vivo they are associated with worse overall survival in some studies”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [73]
PIK3CA co-mutations do not appear to affect response rates to first- or second-line EGFR TKI therapy.
“do not appear to impact response rates and progression-free survival with first or second line EGFR TKI therapy73, 115, 123”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [73]
PIK3CA co-mutations do not appear to affect progression-free survival with first- or second-line EGFR TKI therapy.
“do not appear to impact response rates and progression-free survival with first or second line EGFR TKI therapy73, 115, 123”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [73]
CTNNB1 mutations occur more frequently in LUAD with EGFR T790M after first- or second-generation EGFR TKI exposure.
“mutations in CTNNB1 have been reported to occur more frequently in LUAD with the EGFRT790M mutation following exposure to first or second generation EGFR TKIs”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [73]
Liquid biopsies cannot capture the full range of mutations that may affect outcomes because of the limited gene panel or other resistance mechanisms.
“However, these noninvasive liquid biopsies cannot identify the full spectrum of mutations possibly affecting clinical outcomes due to the limited number of genes analyzed (typically 68 to 70 genes) or other concomitant resistant mechanisms.9,27,30”
From Concurrent Genetic Alterations Predict the Progression to Target Therapy in EGFR-Mutated Advanced NSCLC (2019) · cites this paper as [9]
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- [11]Yu H Analysis of Mechanisms of Acquired Resistance to EGFR TKI therapy in 155 patients with EGFR-mutant Lung Cancers Clin Cancer Res 19 2240 2247 2013 23470965 PMC3630270
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- Authors
- 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., Giannikopoulos, P., Simmons, A. D., Mack, P. C., Gandara, D. R., Husain, H., Doebele, R. C., Riess, J. W., Diehn, M., Swanton, C., & Bivona, T. G.
- Affiliations
- University of California, San Francisco (US)
- The Francis Crick Institute (GB)
- Stanford Medicine (US)
- University of Colorado Anschutz (US)
- Guardant (United States) (US)
- Clovis Oncology (United States) (US)
- UC Davis Comprehensive Cancer Center (US)
- University of California San Diego (US)
- Corresponding author
- Swanton, Charles
- Bivona, Trever G
- ORCID
- Blakely, Collin M
- Watkins, Thomas B K
- Wu, Wei
- Gini, Beatrice
- Chabon, Jacob J
- McCoach, Caroline E
- McGranahan, Nicholas
- Wilson, Gareth A
- Birkbak, Nicolai J
- Rotow, Julia
- Maynard, Ashley
- Wang, Victoria
- Gubens, Matthew A
- Banks, Kimberly C
- Lanman, Richard B
- 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
- Venue
- Nature Genetics
- Published
- 2017-11-06
- Volume
- 49
- Issue
- 12
- Pages
- 1693-1704
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5709185
- OpenAlex
- W2766316939
- Cited by
- 571
- References
- 39
- Citations by year
- 2026: 32 · 2025: 54 · 2024: 42 · 2023: 79 · 2022: 63 · 2021: 93 · 2020: 89 · 2019: 70 · 2018: 49
- FWCI
- 47.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Francis Crick Institute (10169)
- Cancer Research UK (20466, 19310, 17786)
- Rosetrees Trust (M231-CD1)
- Medical Research Council (MR/P014712/1)
- National Cancer Institute (R01CA169338, DP2CA174497, U01CA217882, R01CA211052, P50CA058187, R01CA204302, U54CA224081)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- EGFR-mutant lung cancer, EGFR inhibitor resistance, cell-free DNA, Wnt/β-catenin signaling, CTNNB1, PIK3CA, CDK4, CDK6, metastasis, combination therapy, advanced lung cancer
- MeSH terms
- Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Neoplasm Staging, Gene Expression Regulation, Neoplastic, Cyclin-Dependent Kinases, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, beta Catenin, Kaplan-Meier Estimate, Class I Phosphatidylinositol 3-Kinases, Wnt Signaling Pathway, Clonal Evolution, ErbB Receptors
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