Abstract
In June 2022, the FDA granted Accelerated Approval to the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib for the treatment of adult and paediatric patients (≥6 years of age) with unresectable or metastatic BRAFV600E-mutant solid tumours, except for BRAFV600E-mutant colorectal cancers. The histology-agnostic approval of dabrafenib plus trametinib marks the culmination of two decades of research into the landscape of BRAF mutations in human cancers, the biochemical mechanisms underlying BRAF-mediated tumorigenesis, and the clinical development of selective RAF and MEK inhibitors. Although the majority of patients with BRAFV600E-mutant tumours derive clinical benefit from BRAF inhibitor-based combinations, resistance to treatment develops in most. In this Review, we describe the biochemical basis for oncogenic BRAF-induced activation of MAPK signalling and pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. We also discuss novel RAF inhibitors and drug combinations designed to delay the emergence of treatment resistance and/or expand the population of patients with BRAF-mutant cancers who benefit from molecularly targeted therapies.
Key points
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The FDA-approved BRAF inhibitors vemurafenib, dabrafenib and encorafenib selectively inhibit activated BRAFV600E/K/R/D monomers (class I BRAF mutants) in cancer cells, which underlies their clinical success and wide therapeutic index.
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Selective inhibitors of BRAF monomers can paradoxically activate RAF proteins that function as dimers and thus enhance ERK signalling in some cancer cells and non-malignant cells.
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BRAF inhibitor resistance is common and manifests through rapid reactivation of ERK signalling, owing to relief of negative feedback mechanisms, that results in adaptive (re)activation of RTK signalling, RAS activation and RAF dimerization, or through selection for alterations such as NRAS mutations, BRAF amplification and expression of BRAF splice variants that promote RAF dimer formation.
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Combinations of monomer-selective BRAF inhibitors and MEK inhibitors are something rare in oncology, in that they are more effective and potentially less toxic than either agent alone.
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Ongoing studies are testing novel RAF inhibitors that effectively inhibit RAF dimers and combination strategies designed to more maximally and durably inhibit ERK signalling or that co-target parallel signalling pathways or other mechanisms of RAF inhibitor resistance.
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Innovations in genomic, transcriptional and proteomic profiling and serial tumour sampling along with novel trial designs will be needed for the efficient clinical testing and deployment of novel RAF inhibitor combination regimens that target adaptive and selective mechanisms of drug resistance.
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Acknowledgements
The work of the authors is supported by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO), Cycle for Survival, the NIH (grants R01 CA229624 and P50 CA092629 to D.B.S.), and the NIH National Cancer Institute (Cancer Center Support Grant P30 CA008748). The authors acknowledge the Memorial Sloan Kettering Cancer Center (MSKCC) Diagnostic Molecular Pathology Service, and the American Association for Cancer Research (AACR) Project GENIE registry and consortium for their commitment to data sharing.
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The authors contributed substantially to all aspects of the preparation of this manuscript. D.B.S. supervised the entire process. N.R. and D.B.S. contributed their clinical and translational expertise on the topic.
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N.R. is on the scientific advisory board (SAB) and owns equity in Beigene, MapKure, Ribon and Zai Labs; is also on the SAB of AstraZeneca, Chugai, Concarlo and Ikena; is a past SAB member of Araxes, Kura, Novartis and Takeda (formerly Millennium); has equity in Effector, Fortress and Kura; is a consultant to Array/Pfizer, Boeringher Ingelheim, Eli Lilly, RevMed, Tarveda and Verustem; and receives research funding from Array/Pfizer, AstraZeneca, Boerhinger Ingelheim and Revmed. D.B.S. has served as a consultant and/or SAB member for BridgeBio, Elsie Biotherapeutics, Fog Pharma, Fore Therapeutics, Function Oncology, Lilly/Loxo Oncology, PaigeAI, Pfizer, Scorpion Therapeutics and Vividion Therapeutics. The other authors declare no competing interests.
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Hanrahan, A.J., Chen, Z., Rosen, N. et al. BRAF — a tumour-agnostic drug target with lineage-specific dependencies. Nat Rev Clin Oncol 21, 224–247 (2024). https://doi.org/10.1038/s41571-023-00852-0
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DOI: https://doi.org/10.1038/s41571-023-00852-0
