BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition
Open accessAbstract
ERK signaling requires RAS-induced RAF dimerization and is limited by feedback. Activated BRAF mutants evade feedback inhibition of RAS by either of two mechanisms. BRAF V600 mutants are activated monomers when RAS activity is low; all other activating BRAF mutants function as constitutive RAS-independent dimers. RAF inhibitors effectively inhibit mutant monomers, but not dimers; their binding to one site in the dimer significantly reduces their affinity for the second. Tumors with non-V600E BRAF mutants are insensitive to these drugs, and increased expression of BRAF V600E dimers causes acquired resistance. A compound that equally inhibits both sites of mutant RAF dimers inhibits tumors driven by either class of mutants or those BRAF V600E tumors with dimer-dependent acquired resistance to monomer-specific inhibitors.
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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 [80]
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- Authors
- Yao, Z., Torres, N. M., Tao, A., Gao, Y., Luo, L., Li, Q., de Stanchina, E., Abdel-Wahab, O., Solit, D. B., Poulikakos, P. I., & Rosen, N.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- New York University (US)
- BeiGene (China) (CN)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Rosen, Neal
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 28
- Issue
- 3
- Pages
- 370-383
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4894664
- OpenAlex
- W1764134105
- Cited by
- 543
- References
- 29
- Citations by year
- 2026: 28 · 2025: 56 · 2024: 59 · 2023: 66 · 2022: 66 · 2021: 51 · 2020: 53 · 2019: 47 · 2018: 53 · 2017: 38 · 2016: 22 · 2015: 2 · 2014: 1
- FWCI
- 16.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA169351, P01CA129243, T32CA062948, P30CA008748)
- 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
- ERK signaling, RAF dimerization, BRAF V600E mutation, RAF inhibitors, acquired drug resistance
- MeSH terms
- Humans, Mutation, ras Proteins, Drug Resistance, Neoplasm, Dimerization, MAP Kinase Signaling System, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf
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