Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma
Open accessAbstract
BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.
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SRC activation has been implicated in innate or acquired resistance to targeted drugs, including cetuximab in KRAS mutant colorectal cancer and BRAF inhibitors in BRAFV600E melanoma.
“SRC activation has been also implicated in innate or acquired resistance to targeted drugs, such as cetuximab in KRAS mutant CRC [32] or BRAFi in BRAFV600E melanoma patients [33, 34]”
From Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer (2025) · cites this paper as [33]
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“…implicated in innate or acquired resistance to targeted drugs, such as cetuximab in KRAS mutant CRC [32] or BRAFi in BRAF V600E melanoma patients [33, 34], thus opening new avenues for potential drug manipulation that may eventually expand treat-ment options and improve the prognosis of these…”
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- Authors
- Girotti, M. R., Lopes, F., Preece, N., Niculescu-Duvaz, D., Zambon, A., Davies, L., Whittaker, S., Saturno, G., Viros, A., Pedersen, M., Suijkerbuijk, B. M. J. M., Menard, D., McLeary, R., Johnson, L., Fish, L., Ejiama, S., Sanchez-Laorden, B., Hohloch, J., Carragher, N., Macleod, K., Ashton, G., Marusiak, A. A., Fusi, A., Brognard, J., Frame, M., Lorigan, P., Marais, R., & Springer, C.
- Affiliations
- Institute of Cancer Research (GB)
- Cancer Research UK Manchester Institute (GB)
- Edinburgh Cancer Research (GB)
- University of Manchester (GB)
- Corresponding author
- Marais, Richard
- Springer, Caroline
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 27
- Issue
- 1
- Pages
- 85-96
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4297292
- OpenAlex
- W2149576348
- Cited by
- 212
- References
- 8
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 10 · 2023: 12 · 2022: 14 · 2021: 24 · 2020: 14 · 2019: 15 · 2018: 21 · 2017: 27 · 2016: 30 · 2015: 31
- FWCI
- 12.04
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-03-13)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc-nd)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by-nc-nd)
- Funders
- Wellcome Trust (096444, 100282, WT1005X, 100282/Z/12/Z)
- Cancer Research UK (C157/A15703, 11566, 17240, 12936, C15759/A12328, 19279, 15703, A17240)
- U.S. Food and Drug Administration
- FP7 Ideas: European Research Council (294440)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- BRAF-mutant melanoma, NRAS-mutant melanoma, pan-RAF inhibitor, Src family kinases, drug resistance, MEK/ERK signaling, receptor tyrosine kinase signaling, patient-derived xenografts
- MeSH terms
- Animals, Antineoplastic Agents, Female, Humans, Melanoma, Melanoma, Experimental, Mice, Nude, Phenylurea Compounds, Pyrazines, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, src-Family Kinases, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Mice
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