Oncogenic mutations of BRAF drive ERK-dependent cancer growth. Physiological ERK activation occurs when activated RAS induces dimerization of RAF, a process limited by negative feedback. Yao et al. show that all activated BRAF mutants evade feedback inhibition owing to RAS-independence: BRAF V600 mutants signal as active monomers and all other BRAF-activating mutants signal as constitutive, RAS-independent dimers. The approved RAF inhibitor, vemurafenib, only inhibits mutant monomers and is ineffective in non-V600E BRAF mutant tumours. The authors identify BGB659, a type II, ATP-competitive RAF inhibitor which can bind RAF dimers and effectively inhibit tumour growth driven by all RAF mutants in mice.
References
Yao, Z. et al. BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition. Cancer Cell 28, 370–383 (2015)
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Crunkhorn, S. New RAF inhibitor with broad activity. Nat Rev Drug Discov 14, 750 (2015). https://doi.org/10.1038/nrd4778
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DOI: https://doi.org/10.1038/nrd4778
