RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling
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Activating BRAF mutants and fusions signal as RAS-independent constitutively active dimers with the exception of BRAF V600 mutant alleles which can function as active monomers 1. Current RAF inhibitors are monomer selective, they potently inhibit BRAF V600 monomers but their inhibition of RAF dimers is limited by induction of negative cooperativity when bound to one site in the dimer 1-3. Moreover, acquired resistance to these drugs is usually due to molecular lesions that cause V600 mutants to dimerize 4-8. We show here that PLX8394, a new RAF inhibitor 9, inhibits ERK signaling by specifically disrupting BRAF-containing dimers, including BRAF homodimers and BRAF-CRAF heterodimers, but not CRAF homodimers or ARAF-containing dimers. Differences in the amino acid residues in the amino (N)-terminal portion of the kinase domain of RAF isoforms are responsible for this differential vulnerability. As a BRAF-specific dimer breaker, PLX8394 selectively inhibits ERK signaling in tumors driven by dimeric BRAF mutants, including BRAF fusions and splice variants as well as BRAF V600 monomers, but spares RAF function in normal cells in which CRAF homodimers can drive signaling. Our work suggests that drugs with these properties will be safe and useful for treating tumors driven by activating BRAF mutants or fusions.
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Plixorafenib blocks ERK signaling in tumors driven by dimeric and monomeric BRAF mutants while sparing normal RAF function.
“Plixorafenib (PLX8394, Fore Biotherapeutics) is a second-generation BRAF inhibitor that blocks ERK signaling in tumors driven by dimeric and monomeric BRAF mutants while sparing normal RAF function, earning it the name “paradox breaker” [7].”
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 [7]
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- Authors
- Yao, Z., Gao, Y., Su, W., Yaeger, R., Tao, J., Na, N., Zhang, Y., Zhang, C., Rymar, A., Tao, A., Timaul, N. M., Mcgriskin, R., Outmezguine, N. A., Zhao, H., Chang, Q., Qeriqi, B., Barbacid, M., de Stanchina, E., Hyman, D. M., Bollag, G., & Rosen, N.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Plexxikon (United States) (US)
- New York University (US)
- Spanish National Cancer Research Centre (ES)
- Corresponding author
- Rosen, Neal
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-12-17
- Volume
- 25
- Issue
- 2
- Pages
- 284-291
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6404779
- OpenAlex
- W2904473855
- Cited by
- 195
- References
- 24
- Citations by year
- 2026: 13 · 2025: 23 · 2024: 29 · 2023: 26 · 2022: 24 · 2021: 26 · 2020: 33 · 2019: 20
- FWCI
- 7.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- GlaxoSmithKline
- Plexxikon
- Nature
- National Institutes of Health (U54OD020355, KL2TR002385)
- National Cancer Institute (P01CA129243, R35CA210085, P30CA008748, T32CA009207, R25CA020449)
- National Center for Advancing Translational Sciences
- 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
- RAF inhibitors, BRAF fusion, BRAF V600, Raf-1, ARAF, ERK signaling, Raf isoforms, Ras-independent signaling, acquired drug resistance, therapeutic window
- MeSH terms
- Heterocyclic Compounds, 2-Ring, Humans, Mutation, Phosphorylation, Sulfonamides, Signal Transduction, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins B-raf, Cell Proliferation, Protein Multimerization
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