Overcoming the Limits of Inhibition: Mutant-Selective BRAF Degraders

Targeted inhibition of mutant BRAF has transformed the management of BRAF-V600-mutant melanoma and other malignancies, with multiple ATP-competitive kinase inhibitors now approved for clinical use. Despite their clinical success, these agents are limited by intrinsic and acquired resistance, paradoxical activation of the MAPK pathway, and dose-limiting toxicities. The development of BRAF-V600X oncoprotein-selective degraders offers a mechanistically distinct therapeutic approach that may bypass several of these liabilities. Thus, the discovery of an orally bioavailable mutant BRAF-selective degrader is highly sought after. In this issue of Cancer Research, Kreger and colleagues developed CFT1946, a clinical-stage, highly potent, RAF family-selective degrader that is effective in various cellular and xenograft models. Importantly, CFT1946 is active in the privileged central nervous system environment, accessing a common site of metastasis for BRAF-mutant melanomas. By eliminating the BRAF-V600X oncoprotein, CFT1946 can overcome RAF dimer- and EGFR-driven resistance to standard inhibitors. Although the mechanism of mutant selectivity is unclear, this compound exhibits a promising therapeutic index by sparing wild-type RAF proteins in cells. As CFT1946 progresses through clinical development, the field of oncoprotein-specific degradation will mature. See related article by Kreger et al., p. 438.