Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF -Mutant Colorectal Cancer
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Abstract
Although recent clinical trials of BRAF inhibitor combinations have demonstrated improved efficacy in BRAF-mutant colorectal cancer, emergence of acquired resistance limits clinical benefit. Here, we undertook a comprehensive effort to define mechanisms underlying drug resistance with the goal of guiding development of therapeutic strategies to overcome this limitation. We generated a broad panel of BRAF-mutant resistant cell line models across seven different clinically relevant drug combinations. Combinatorial drug treatments were able to abrogate ERK1/2 phosphorylation in parental-sensitive cells, but not in their resistant counterparts, indicating that resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway. Genotyping of resistant cells identified gene amplification of EGFR, KRAS, and mutant BRAF, as well as acquired mutations in KRAS, EGFR, and MAP2K1. These mechanisms were clinically relevant, as we identified emergence of a KRAS G12C mutation and increase of mutant BRAF V600E allele frequency in the circulating tumor DNA of a patient at relapse from combined treatment with BRAF and MEK inhibitors. To identify therapeutic combinations capable of overcoming drug resistance, we performed a systematic assessment of candidate therapies across the panel of resistant cell lines. Independent of the molecular alteration acquired upon drug pressure, most resistant cells retained sensitivity to vertical MAPK pathway suppression when combinations of ERK, BRAF, and EGFR inhibitors were applied. These therapeutic combinations represent promising strategies for future clinical trials in BRAF-mutant colorectal cancer. Cancer Res; 76(15); 4504–15. ©2016 AACR.
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The association of BRAF or ARID1A co-alterations with shorter progression-free survival is mechanistically plausible and consistent with studies implicating these genes in EGFR inhibitor resistance.
“Our observation that BRAF or ARID1A co-alterations are associated with shorter progression-free survival is mechanistically plausible and consistent with studies implicating these genes in EGFR inhibitor resistance. 23-27”
From Sotorasib with panitumumab in chemotherapy-refractory KRASG12C-mutated colorectal cancer: a phase 1b trial (2024) · cites this paper as [27]
The Results section reports that BRAF V600E amplification was found in cells resistant to MEK-plus-EGFR inhibition and that overexpressing mutant BRAF conferred resistance to that combination. This supports a mechanistic link for BRAF, but our copy does not implicate ARID1A in EGFR inhibitor resistance. The shorter progression-free survival association is presented as the citing authors’ own observation, not a finding attributed to this source. (LLM, conf=0.87)
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- Authors
- Oddo, D., Sennott, E. M., Barault, L., Valtorta, E., Arena, S., Cassingena, A., Filiciotto, G., Marzolla, G., Elez, E., van Geel, R. M. J. M., Bartolini, A., Crisafulli, G., Boscaro, V., Godfrey, J. T., Buscarino, M., Cancelliere, C., Linnebacher, M., Corti, G., Truini, M., Siravegna, G., Grasselli, J., Gallicchio, M., Bernards, R., Schellens, J. H. M., Tabernero, J., Engelman, J. A., Sartore-Bianchi, A., Bardelli, A., Siena, S., Corcoran, R. B., & Di Nicolantonio, F.
- Affiliations
- Candiolo Cancer Institute (IT)
- Massachusetts General Hospital (US)
- Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT)
- 5Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
- 6The Netherlands Cancer Institute, Amsterdam, the Netherlands.
- University of Turin (IT)
- University of Rostock (DE)
- IFOM (IT)
- Universitat Autònoma de Barcelona (ES)
- The Netherlands Cancer Institute (NL)
- Harvard University (US)
- 4Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
- University of Milan (IT)
- 1Department of Oncology, University of Torino, Candiolo, Torino, Italy.
- ORCID
- Oddo, Daniele
- Barault, Ludovic
- Valtorta, Emanuele
- Arena, Sabrina
- Cassingena, Andrea
- Bartolini, Alice
- Crisafulli, Giovanni
- Boscaro, Valentina
- Godfrey, Jason T.
- Linnebacher, Michael
- Corti, Giorgio
- Siravegna, Giulia
- Grasselli, Julieta
- Gallicchio, Margherita
- Bernards, René
- Schellens, Jan H.M.
- Tabernero, Josep
- Engelman, Jeffrey A.
- Bardelli, Alberto
- Siena, Salvatore
- Corcoran, Ryan B.
- Venue
- Cancer Research
- Published
- 2016-07-31
- Volume
- 76
- Issue
- 15
- Pages
- 4504-4515
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC4970882
- OpenAlex
- W2420593137
- Cited by
- 121
- References
- 9
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 13 · 2023: 8 · 2022: 12 · 2021: 8 · 2020: 14 · 2019: 15 · 2018: 14 · 2017: 16 · 2016: 5
- FWCI
- 8.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- European Commission (635342, 16788, 115749, 602901)
- Ministero della Salute
- Ministero dell’Istruzione, dell’Università e della Ricerca
- KWF Kankerbestrijding
- Fondazione Umberto Veronesi
- Associazione Italiana per la Ricerca sul Cancro (16788, 17707, IGn. 16788, IG n. 17707)
- Fondazione Oncologia Niguarda Onlus
- National Institutes of Health (CA127003)
- Stand Up To Cancer (P50 CA127003)
- National Cancer Institute (P50CA127003, R01CA208437, CA127003, K08CA166510)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- BRAF-mutant colorectal cancer, acquired drug resistance, BRAF inhibitors, MEK inhibitors, ERK inhibitor, EGFR inhibitors, MAPK pathway reactivation, KRAS G12C mutation, EGFR amplification, KRAS mutation, MAP2K1 mutation, circulating tumor DNA, combination therapy
- MeSH terms
- Gene Amplification, Humans, Colorectal Neoplasms, Signal Transduction, Gene Dosage, Drug Resistance, Neoplasm, Proto-Oncogene Proteins B-raf
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