Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAF V600E-Mutant Colorectal Cancer
Open accessPublished version of a preprint
Abstract
Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism. Significance: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 428–43. ©2018 AACR. See related commentary by Janku, p. 389. See related article by Hazar-Rethinam et al., p. 417. This article is highlighted in the In This Issue feature, p. 371
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Combination therapies to suppress adaptive feedback proved key to optimizing the frequency and durability of response in each tumor type.
“Still, in all cases, combination therapies to suppress adaptive feedback proved key to optimizing the frequency and durability of response in each tumor type (34,50,51).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [34]
The Abstract and Discussion report that targeting adaptive feedback improved response rates in BRAF V600E–mutant colorectal cancer. But the Discussion says response duration remained poor and further optimization was needed. This study therefore does not establish that the combination optimized durability, or outcomes in every tumor type. (LLM, conf=0.87)
Experimental — accuracy not yet measuredRAS/RAF-mutated CRC targeted therapies have been largely ineffective, likely due to complex resistance mechanisms such as intrinsic and adaptive resistance.
“Although RAS/RAF-mutated CRC has been targeted for the development of therapeutic inhibitors, they have been largely ineffective, likely due to complex resistance mechanisms such as intrinsic and adaptive resistance [5–12].”
From An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy (2022) · cites this paper as [10]
The Introduction reports that single-agent BRAF inhibitors had little efficacy in BRAF V600E-mutant CRC and describes adaptive MAPK reactivation as a proposed explanation. The Discussion identifies MAPK reactivation as a mechanism of primary and acquired resistance. The paper does not establish that targeted therapies have been largely ineffective across RAS/RAF-mutated CRC generally; its clinical study concerns BRAF V600E-mutant CRC. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCombined BRAF and EGFR inhibition significantly improves response rates in BRAF V600E metastatic CRC patients (10% or 19%) and has become FDA-approved standard of care.
“Recent clinical trials report that combined BRAF and EGFR inhibition significantly improves response rates in BRAF (V600E) metastatic CRC patients (10% or 19%) [10, 13], and has now become the FDA-approved, standard of care.”
From An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy (2022) · cites this paper as [10]
The Results (Efficacy; page not provided) report a 10% confirmed response rate with combined BRAF and EGFR inhibition in patients with BRAF V600E colorectal cancer. They report 19 responders—not a 19% response rate—in the arm that also received MEK inhibition. The paper does not establish a statistically significant improvement or say this CRC treatment was FDA-approved standard of care; its Introduction discusses FDA approval for other cancers. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAdaptive resistance can rapidly induce drug resistance to targeted therapy in tumors that are natively sensitive.
“Thus, AR can rapidly induce drug resistance to targeted therapy in tumors that are natively “sensitive”.”
From An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy (2022) · cites this paper as [10]
The Introduction describes adaptive feedback that restores MAPK signaling after initial suppression by a BRAF inhibitor, and the Discussion links MAPK reactivation to resistance in BRAF V600E colorectal cancer (page numbers unavailable). The claim extends this finding to natively sensitive tumors generally, whereas the paper emphasizes that these colorectal tumors respond poorly to BRAF inhibitor monotherapy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCombined EGFR and BRAF blockade proved synthetic lethality in preclinical models of BRAFV600E CRC and modestly improves survival of patients with advanced disease.
“Combined EGFR and BRAF blockade proved synthetic lethality in preclinical models of BRAFV600E CRC and modestly improves survival of patients with advanced disease [7, 8, 15–17].”
From Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer (2025) · cites this paper as [15]
The Introduction reports improved MAPK suppression and tumor regression with combined BRAF and EGFR inhibition in preclinical BRAFV600E CRC xenografts, but does not establish synthetic lethality. The Discussion describes modest clinical activity, and the Results > Efficacy reports survival times; without a survival comparator, this paper does not establish that the combination improves patient survival. (LLM, conf=0.88)
Experimental — accuracy not yet measured
The combination of BRAF and EGFR only suppresses signaling in a subset of patients.
“and that the combination of BRAF and EGFR only suppresses signaling in a subset of patients (34).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [34]
Other RTKs can drive feedback in an EGFR-independent manner.
“However, preclinical and clinical data have demonstrated that other RTKs can drive feedback in an EGFR-independent manner”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [34]
In BRAFV600 colorectal cancer, targeting EGFR in combination with BRAF inhibition has led to an improvement in clinical efficacy.
“Indeed, in BRAFV600 colorectal cancer, targeting EGFR—the RTK thought to be the primary driver of feedback reactivation from preclinical studies—in combination with BRAF inhibition, has led to an improvement in clinical efficacy (34–39).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [34]
The triple combination of BRAF, EGFR, and MEK inhibition has shown higher response rates and improved efficacy in patients with BRAF-mutant CRC.
“the triple combination of BRAF, EGFR, and MEK inhibition has shown higher response rates and improved efficacy in patients with BRAF-mutant CRC [238,239].”
From Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer (2025) · cites this paper as [238]
BRAFV600E mutations cause RAS-independent activation of MAPK signaling, amplifying proliferative signals and driving cancer progression.
“BRAFV600E mutations result in RAS-independent activation of the MAPK signaling pathway, amplifying proliferative signals and driving cancer progression [4].”
From Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer (2026) · cites this paper as [4]
Pre-clinical studies and early trials have demonstrated improved responses to combined MEK and BRAF inhibition.
“Pre-clinical studies and early trials have demonstrated improved responses to combined MEK and BRAF inhibition [37,38].”
From Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer (2024) · cites this paper as [38]
Combination treatment with EGFRi and MEKi produced limited antitumor efficacy in CRC patients.
“Combination treatment with EGFRi and MEKi produced limited antitumor efficacy in CRC patients [34].”
From Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer (2022) · cites this paper as [34]
Because K-RasG12C inhibitors are highly specific for the mutant protein, drug combinations involving K-RasG12C inhibitors would likely be better tolerated in patients.
“However, since K-RasG12C inhibitors are highly specific for the mutant protein, drug combinations involving K-RasG12C inhibitors would likely be better-tolerated in patients.83”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [83]
In early-phase clinical trials for BRAF V600E mutant colorectal cancer, co-inhibition of EGFR and RAF, with or without downstream MEK inhibition, is required to induce durable complete tumor regression.
“In early-phase clinical trials for BFAFV600E mutant colorectal cancer where EGFR is the dominant RTK driving tumor growth, co-inhibition of EGFR and RAF, with or without downstream MEK inhibition, are required to induce durable complete tumor regression.83”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [83]
In BRAF mutant colorectal cancers, EGFR-mediated adaptive resistance severely limits the response to single-agent BRAF inhibition as well as combined BRAF and MEK inhibition.
“In BRAF mutant colorectal cancers, EGFR-mediated adaptive resistance severely limits the response to single-agent BRAF inhibition as well as combined BRAF and MEK inhibition; however, increased response rates to the triple combination of BRAF (dabrafenib), EGFR (panitumumab), and MEK inhibition (trametinib) have been observed in the clinic [105].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [105]
Increased response rates to the triple combination of BRAF (dabrafenib), EGFR (panitumumab), and MEK inhibition (trametinib) have been observed in the clinic in BRAF mutant colorectal cancers.
“In BRAF mutant colorectal cancers, EGFR-mediated adaptive resistance severely limits the response to single-agent BRAF inhibition as well as combined BRAF and MEK inhibition; however, increased response rates to the triple combination of BRAF (dabrafenib), EGFR (panitumumab), and MEK inhibition (trametinib) have been observed in the clinic [105].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [105]
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Comprehensive review of targeted therapy for colorectal cancer
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Encorafenib, Binimetinib, and Cetuximab in <i>BRAF</i> V600E–Mutated Colorectal Cancer
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Self-citationVertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition
Ryan, M. B., Fece de la Cruz, F., Phat, S., Myers, D. T., Wong, E., Shahzade, H. A., Hong, C. B., & Corcoran, R. B. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-3523 · Cited by 496 · see citing works
“However, preclinical and clinical data have demonstrated that other RTKs can drive feedback in an EGFRindependent manner, and that the combination of BRAF and EGFR only suppresses signaling in a subset of patients (34).”
BackgroundSelf-citationTherapeutic strategies to target RAS-mutant cancers
Ryan, M. B., & Corcoran, R. B. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0105-0 · Cited by 420 · see citing works
Self-citationTranslational and therapeutic evaluation of RAS-GTP inhibition by RMC-6236 in RAS-driven cancers
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Biomarker-guided therapy for colorectal cancer: strength in complexity
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Van Cutsem, E., Huijberts, S., Grothey, A., Yaeger, R., Cuyle, P.-J., Elez, E., Fakih, M., Montagut, C., Peeters, M., Yoshino, T., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.18.02459 · Cited by 224 · see citing works
Self-citationAhmed, T. A., Adamopoulos, C., Karoulia, Z., Wu, X., Sachidanandam, R., Aaronson, S. A., & Poulikakos, P. I. (2019) · Cell Reports · doi:10.1016/j.celrep.2018.12.013 · Cited by 214 · see citing works
Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer
Molina-Arcas, M., Moore, C., Rana, S., van Maldegem, F., Mugarza, E., Romero-Clavijo, P., Herbert, E., Horswell, S., Li, L.-S., Janes, M. R., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aaw7999 · Cited by 203 · see citing works
Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer
Cabanos, H. F., & Hata, A. N. (2021) · Cancers · doi:10.3390/cancers13112666 · Cited by 189 · see citing works
MEK inhibitors activate Wnt signalling and induce stem cell plasticity in colorectal cancer
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KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne?
Nagasaka, M., Li, Y., Sukari, A., Ou, S.-H. I., Al-Hallak, M. N., & Azmi, A. S. (2020) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2020.101974 · Cited by 185 · see citing works
KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy
Ryan, M. B., Coker, O., Sorokin, A., Fella, K., Barnes, H., Wong, E., Kanikarla, P., Gao, F., Zhang, Y., Zhou, L., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110993 · Cited by 177 · see citing works
Self-citationCombinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling
Liu, C., Lu, H., Wang, H., Loo, A., Zhang, X., Yang, G., Kowal, C., Delach, S., Wang, Y., Goldoni, S., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-2718 · Cited by 167 · see citing works
Encorafenib, Cetuximab, and mFOLFOX6 in <i>BRAF</i> -Mutated Colorectal Cancer
Elez, E., Yoshino, T., Shen, L., Lonardi, S., Van Cutsem, E., Eng, C., Kim, T. W., Wasan, H. S., Desai, J., Ciardiello, F., et al. (2025) · New England Journal of Medicine · doi:10.1056/nejmoa2501912 · Cited by 166 · see citing works
Self-citationMolecular Pathways and Mechanisms of BRAF in Cancer Therapy
Poulikakos, P. I., Sullivan, R. J., & Yaeger, R. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-2138 · Cited by 145 · see citing works
Self-citationBRAF — a tumour-agnostic drug target with lineage-specific dependencies
Hanrahan, A. J., Chen, Z., Rosen, N., & Solit, D. B. (2024) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00852-0 · Cited by 136 · see citing works
Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer
Underwood, P. W., Ruff, S. M., & Pawlik, T. M. (2024) · Cells · doi:10.3390/cells13030245 · Cited by 130 · see citing works
Harnessing the predictive power of preclinical models for oncology drug development
Honkala, A., Malhotra, S. V., Kummar, S., & Junttila, M. R. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00301-6 · Cited by 121 · see citing works
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<i>BRAF</i> -Mutated Advanced Colorectal Cancer: A Rapidly Changing Therapeutic Landscape
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Self-citationMechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer
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“However, the triple combination of BRAF, EGFR, and MEK inhibition has shown higher response rates and improved efficacy in patients with BRAF -mutant CRC [238,239].”
The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer
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“Combination treatment with EGFRi and MEKi produced limited antitumor efficacy in CRC patients [34].”
BackgroundOvercoming Resistance to Drugs Targeting KRAS Mutation
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Overcoming adaptive resistance to KRAS inhibitors through vertical pathway targeting
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Self-citationXu, T., Wang, X., Wang, Z., Deng, T., Qi, C., Liu, D., Li, Y., Ji, C., Li, J., & Shen, L. (2022) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359221105022 · Cited by 38 · see citing works
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“For example, while MEKi (selumetinib, AZD6244) may mediate feedback activation of EGFR in BRAF (V600E) CRC cells [9], no clinical responses were observed in CRC patients treated with combination of MEKi with EGFRi [10].”
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Redefining Colorectal Cancer by Tumor Biology
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Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer
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“BRAF V600E mutations result in RAS-independent activation of the MAPK signaling pathway, amplifying proliferative signals and driving cancer progression [4].”
- Authors
- Corcoran, R. B., André, T., Atreya, C. E., Schellens, J. H. M., Yoshino, T., Bendell, J. C., Hollebecque, A., McRee, A. J., Siena, S., Middleton, G., Muro, K., Gordon, M. S., Tabernero, J., Yaeger, R., O'Dwyer, P. J., Humblet, Y., De Vos, F., Jung, A. S., Brase, J. C., Jaeger, S., Bettinger, S., Mookerjee, B., Rangwala, F., & Van Cutsem, E.
- Affiliations
- Harvard University (US)
- Sorbonne Université (FR)
- University of California, San Francisco (US)
- The Netherlands Cancer Institute (NL)
- 5National Cancer Center Hospital East, Chiba, Japan.
- Sarah Cannon (US)
- Institut Gustave Roussy (FR)
- University of North Carolina at Chapel Hill (US)
- University of Milan (IT)
- University of Birmingham (GB)
- Aichi Cancer Center (JP)
- Pinnacle Oncology Hematology (US)
- Vall d'Hebron Hospital Universitari (ES)
- Memorial Sloan Kettering Cancer Center (US)
- University of Pennsylvania (US)
- 16St-Luc University Hospital, Brussels, Belgium.
- 17Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
- Amgen (United States) (US)
- Novartis (Switzerland) (CH)
- 21Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
- 22University Hospitals Leuven and KU Leuven, Leuven, Belgium.
- Corresponding author
- Corcoran, Ryan B.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2018-04-01
- Volume
- 8
- Issue
- 4
- Pages
- 428-443
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC5882509
- OpenAlex
- W2791410762
- Semantic Scholar
- a7c5a90c85d510482eee8146245f086ee2ca6766
- Cited by
- 592
- References
- 53
- Citations by year
- 2026: 42 · 2025: 58 · 2024: 52 · 2023: 76 · 2022: 69 · 2021: 82 · 2020: 107 · 2019: 77 · 2018: 29
- FWCI
- 28.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Digital Access to Libraries (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Damon Runyon Cancer Research Foundation (Damon Runyon) (Clinical Investigator Award)
- HHS | NIH | National Cancer Institute (NCI) (P50CA127003, R01CA208437)
- American Association for Cancer Research (AACR) (SU2C-AACR-DT22-17)
- 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 › Oncology › Colorectal Cancer Surgical Treatments
- Keywords
- BRAF V600E mutation, colorectal cancer, dabrafenib, panitumumab, trametinib, MEK inhibition, EGFR inhibition, BRAF inhibition, MAPK signaling, acquired drug resistance, KRAS mutation, NRAS mutation, cell-free DNA, pharmacodynamic biomarkers, combination therapy
- MeSH terms
- Panitumumab, Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Imidazoles, Male, Oximes, Pyridones, Pyrimidinones, Colorectal Neoplasms, Drug Resistance, Neoplasm, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, ErbB Receptors
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