Antitumor Activity of BRAF Inhibitor Vemurafenib in Preclinical Models of BRAF-Mutant Colorectal Cancer
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Abstract
The protein kinase BRAF is a key component of the RAS–RAF signaling pathway which plays an important role in regulating cell proliferation, differentiation, and survival. Mutations in BRAF at codon 600 promote catalytic activity and are associated with 8% of all human (solid) tumors, including 8% to 10% of colorectal cancers (CRC). Here, we report the preclinical characterization of vemurafenib (RG7204; PLX4032; RO5185426), a first-in-class, specific small molecule inhibitor of BRAFV600E in BRAF-mutated CRC cell lines and tumor xenograft models. As a single agent, vemurafenib shows dose-dependent inhibition of ERK and MEK phosphorylation, thereby arresting cell proliferation in BRAFV600-expressing cell lines and inhibiting tumor growth in BRAFV600E bearing xenograft models. Because vemurafenib has shown limited single-agent clinical activity in BRAFV600E-mutant metastatic CRC, we therefore explored a range of combination therapies, with both standard agents and targeted inhibitors in preclinical xenograft models. In a BRAF-mutant CRC xenograft model with de novo resistance to vemurafenib (RKO), tumor growth inhibition by vemurafenib was enhanced by combining with an AKT inhibitor (MK-2206). The addition of vemurafenib to capecitabine and/or bevacizumab, cetuximab and/or irinotecan, or erlotinib resulted in increased antitumor activity and improved survival in xenograft models. Together, our findings suggest that the administration of vemurafenib in combination with standard-of-care or novel targeted therapies may lead to enhanced and sustained clinical antitumor efficacy in CRCs harboring the BRAFV600E mutation. Cancer Res; 72(3); 779–89. ©2011 AACR.
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BRAF inhibitors have proven ineffective as single agents due to adaptive feedback re-activation of the MAPK and other signaling pathways.
“BRAF inhibitors have proven ineffective as single agents due to adaptive feedback re-activation of the MAPK and other signaling pathways [5–13, 38].”
From Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer (2025) · cites this paper as [9]
The Discussion reports modest clinical efficacy for single-agent vemurafenib in BRAF-mutant metastatic colorectal cancer and proposes that alternative survival pathways may limit its effect. It does not establish adaptive feedback reactivation of MAPK as the cause; in the resistant RKO cells, vemurafenib still reduced MEK and ERK phosphorylation. The claim also generalizes beyond the colorectal cancer setting studied here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCombined inhibition of EGFR and BRAF can be synergistic in BRAF-mutant colorectal cancers.
“preclinical studies have provided a proof of principle that the combined inhibition of EGFR and BRAF can be synergistic in BRAF-mutant CRCs”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [60]
Best responses of colorectal cancer cell xenografts to combined EGFR and BRAF inhibition were only disease stabilizations or mild tumor regressions.
“the best responses of CRC cell xenografts to such combinations were only disease stabilizations or mild tumor regressions [52, 58-60].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [60]
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- Authors
- Yang, H., Higgins, B., Kolinsky, K., Packman, K., Bradley, W. D., Lee, R. J., Schostack, K., Simcox, M. E., Kopetz, S., Heimbrook, D., Lestini, B., Bollag, G., & Su, F.
- Affiliations
- Plexxikon (United States) (US)
- Corresponding author
- Su, Fei
- Venue
- Cancer Research
- Published
- 2012-01-31
- Volume
- 72
- Issue
- 3
- Pages
- 779-789
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2096024381
- Cited by
- 216
- References
- 45
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 7 · 2023: 11 · 2022: 6 · 2021: 10 · 2020: 15 · 2019: 9 · 2018: 16 · 2017: 11 · 2016: 24 · 2015: 27 · 2014: 16 · 2013: 34 · 2012: 20
- FWCI
- 11.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (KL2TR000370)
- National Center for Advancing Translational Sciences
- 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
- vemurafenib, BRAF V600E mutation, BRAF-mutant colorectal cancer, Ras/Raf signaling, combination therapy, capecitabine, bevacizumab, cetuximab, irinotecan, erlotinib, vemurafenib resistance, tumor xenograft models
- MeSH terms
- Bevacizumab, Cetuximab, Capecitabine, Erlotinib Hydrochloride, Irinotecan, Vemurafenib, Animals, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Deoxycytidine, Dose-Response Relationship, Drug, Fluorouracil, Humans, Indoles, Mice, Nude, Mutation, Phosphorylation, Quinazolines, Sulfonamides, Blotting, Western, Colorectal Neoplasms, Drug Resistance, Neoplasm, HT29 Cells, Area Under Curve, Mitogen-Activated Protein Kinases, Xenograft Model Antitumor Assays, HCT116 Cells, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Cell Proliferation, Mice, Kaplan-Meier Estimate, Antibodies, Monoclonal, Humanized
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