Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition
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Abstract
BRAF V600E colorectal cancers are insensitive to RAF inhibitor monotherapy due to feedback reactivation of receptor tyrosine kinase signaling. Combined RAF and EGFR inhibition exerts a therapeutic effect, but resistance invariably develops through undefined mechanisms. In this study, we determined that colorectal cancer progression specimens invariably harbored lesions in elements of the RAS–RAF–MEK–ERK pathway. Genetic amplification of wild-type RAS was a recurrent mechanism of resistance in colorectal cancer patients that was not seen in similarly resistant melanomas. We show that wild-type RAS amplification increases receptor tyrosine kinase-dependent activation of RAS more potently in colorectal cancer than in melanoma and causes resistance only in the former. Currently approved RAF inhibitors inhibit RAF monomers but not dimers. All the drug-resistant lesions we identified activate BRAF V600E dimerization directly or by elevating RAS-GTP. Overall, our results show that mechanisms of resistance converge on formation of RAF dimers and that inhibiting EGFR and RAF dimers can effectively suppress ERK-driven growth of resistant colorectal cancer. Cancer Res; 77(23); 6513–23. ©2017 AACR.
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Adaptive 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 [8]
The Discussion (page unavailable) links adaptive resistance to RAF inhibitors in colorectal cancer with rapid acquired resistance when RAS expression is high. The claim omits that condition and generalizes the finding to targeted therapy and tumors more broadly. (LLM, conf=0.86)
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 [8]
The Abstract reports that BRAF V600E CRC is insensitive to RAF-inhibitor monotherapy, and the Introduction says resistance develops after initially effective combined RAF/EGFR inhibition. The Discussion also describes adaptive resistance. The claim is broader than this evidence: the paper focuses on BRAF V600E CRC, not RAS/RAF-mutated CRC therapies generally, and it does not establish that all such therapies have been largely ineffective. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMultiple mechanisms of acquired resistance to KRASG12C inhibitors have been identified, largely converging on reactivation of the RAS pathway or activation of parallel signaling pathways such as PI3K/mTOR.
“Multiple mechanisms of acquired resistance have been identified, which largely converge on re-activation of the RAS pathway or alternatively activate parallel signaling pathways such as the PI3K/mTOR pathway10–14.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [12]
The Results (page not supplied) identify several acquired resistance alterations in the RAS/RAF pathway, supporting the pathway-reactivation part of the claim. But this paper studies resistance to BRAF V600E–targeted treatment in colorectal cancer, not KRAS G12C inhibitors, and the cited passages do not establish PI3K/mTOR activation as an alternative mechanism. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBRAF V600E CRC have limited sensitivity to single agent RAF inhibitors, and this is a result of an adaptive response selectively triggered in CRC.
“We and others previously reported that BRAF V600E CRC have limited sensitivity to single agent RAF inhibitors, and this is a result of an adaptive response selectively triggered in CRC(16-18).”
From EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer. (2020) · cites this paper as [18]
The mechanisms underlying differential sensitivity to KRASG12C inhibition are less well understood.
“While previous studies have characterized acquired resistance to KRASG12C inhibition and identified causal mutations and non-genetic mechanisms including RTK activation and epithelial-to-mesenchymal transition11–14,35, the mechanisms underlying differential sensitivity to KRASG12C inhibition are less well understood.”
From Combined inhibition of KRASG12C and mTORC1 kinase is synergistic in non-small cell lung cancer (2024) · cites this paper as [12]
The citation is attached to the preceding claim about studies of acquired resistance to KRASG12C inhibition; the statement that differential sensitivity is less well understood is the citing authors’ own framing. The source’s Results and Discussion instead examine resistance to BRAF V600E and RAF/EGFR inhibition. Searches for KRASG12C inhibition and differential sensitivity found no passage addressing either point. (LLM, conf=0.77)
Experimental — accuracy not yet measured
BRAF (V600E) and MAP2K1/MEK1 (K57T, K57N, I99_K104 deletion, and E102_I103 deletion) can cause acquired drug resistance.
“For instance, BRAF (V600E) and MAP2K1/MEK1 (K57T, K57N, I99_K104 deletion, and E102_I103 deletion) can also cause acquired drug resistance [94, 108–111].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [108]
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- Authors
- Yaeger, R., Yao, Z., Hyman, D. M., Hechtman, J. F., Vakiani, E., Zhao, H., Su, W., Wang, L., Joelson, A., Cercek, A., Baselga, J., de Stanchina, E., Saltz, L., Berger, M. F., Solit, D. B., & Rosen, N.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- 2Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York.
- Corresponding author
- Rosen, Neal
- ORCID
- Venue
- Cancer Research
- Published
- 2017-11-30
- Volume
- 77
- Issue
- 23
- Pages
- 6513-6523
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC5712250
- OpenAlex
- W2760461398
- Cited by
- 94
- References
- 50
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 14 · 2023: 5 · 2022: 14 · 2021: 11 · 2020: 11 · 2019: 9 · 2018: 8
- FWCI
- 3.13
- 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)
- Funders
- National Cancer Institute (R01CA169351, P01CA129243, R35CA210085, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- BRAF V600E mutation, acquired drug resistance, RAF dimerization, RAF inhibitors, colorectal cancer, RAS/MAPK pathway, EGFR inhibition, receptor tyrosine kinase signaling, Ras-GTP
- MeSH terms
- Animals, Antineoplastic Agents, Colonic Neoplasms, Humans, Melanoma, Mice, Nude, Mice, SCID, ras Proteins, HT29 Cells, Dimerization, Monomeric GTP-Binding Proteins, Cell Line, Tumor, Protein Kinase Inhibitors, raf Kinases, Proto-Oncogene Proteins B-raf, Mice, ErbB Receptors
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