Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS
Open accessAbstract
Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants-those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.
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BRAF activating mutations have been classified into three groups defined by their functional effects on the protein product, which consequently determines their response to different inhibitors.
“BRAF activating mutations have been classified into three groups defined by their functional effects on the protein product80,81, which consequently determines their response to different inhibitors82,83”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [81]
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- Authors
- Yao, Z., Yaeger, R., Rodrik-Outmezguine, V. S., Tao, A., Torres, N. M., Chang, M. T., Drosten, M., Zhao, H., Cecchi, F., Hembrough, T., Michels, J., Baumert, H., Miles, L., Campbell, N. M., de Stanchina, E., Solit, D. B., Barbacid, M., Taylor, B. S., & Rosen, N.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- New York University (US)
- Spanish National Cancer Research Centre (ES)
- NantOmics LLC (United States) (US)
- Université Paris-Sud (FR)
- Hôpital Paris Saint-Joseph (FR)
- Corresponding author
- Rosen, Neal
- ORCID
- Venue
- Nature
- Published
- 2017-08
- Volume
- 548
- Issue
- 7666
- Pages
- 234-238
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5648058
- OpenAlex
- W2739964468
- Cited by
- 562
- References
- 18
- Citations by year
- 2026: 48 · 2025: 53 · 2024: 69 · 2023: 67 · 2022: 69 · 2021: 66 · 2020: 73 · 2019: 60 · 2018: 45 · 2017: 11
- FWCI
- 21.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (U54 ODSS020355, U54OD020355)
- National Cancer Institute (R01CA204749, R01CA169351, P01CA129243, R35CA210085, R01CA180037, P30CA008748)
- National Institute of General Medical Sciences (T32GM007175)
- 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 mutation, Ras activation, Raf-1, receptor tyrosine kinase inhibitors, melanoma, lung adenocarcinoma, colorectal cancer
- MeSH terms
- Vemurafenib, Animals, Enzyme Activation, Female, Humans, Indoles, Melanoma, Mutation, Neurofibromatosis 1, Pyridones, Pyrimidinones, Sulfonamides, Oncogene Protein p21(ras), Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, NIH 3T3 Cells, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins B-raf, Mice, Protein Multimerization
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