Mechanism-based strategies to forestall resistance in BRAF-mutant melanoma

Overcoming drug resistance is a major challenge in targeted therapy. The discovery that a large number of tumors, including the majority of melanomas, depend on hyperactivated, mutant BRAF, led to the development of RAF inhibitors to be used as potential therapeutics. RAF inhibitors vemurafenib and dabrafenib have elicited responses and extended survival of patients with BRAF(V600E) tumors, but there is variability in both the extent and the duration of patient responses and acquired resistance almost universally develops. Work by us and others suggested that tumor sensitivity, certain toxicities and common mechanisms of resistance to RAF inhibitors are associated to the unique biochemical properties of these drugs, as a result of critical differences in the mode of activation and signaling between the wild-type and the mutant form of BRAF kinase. However, a detailed understanding of underlying mechanisms is lacking. Recently, novel RAF inhibitors with distinct biochemical properties compared to vemurafenib and dabrafenib have entered preclinical or clinical development, but the most suitable clinical context for potential therapeutic application of these compounds is unknown. The goal of this proposal is it elucidate the detailed mechanism of RAF inhibitor action and help develop compounds and strategies to target BRAF(V600E) melanomas more effectively, with more durable responses and less on-target toxicities. By integrating cellular, biochemical and structural analysis, we have developed a model that predicts the biochemical properties of RAF inhibitors according to their structural properties. Based on our model and our preliminary preclinical work, we propose that a class of next generation RAF inhibitors will be particularly effective in overcoming drug resistance, alone, or as part of a combinatorial strategy with current standard therapies in BRAF-mutant melanoma. Thus, our work directly links the structural properties of RAF inhibitors to their biochemical