The study identifies a novel mechanism of RAF inhibitor resistance in melanomas with mutant BRAF(V600E). Resistance is mediated by the expression of a 61kd variant form of BRAF(V600E) that lacks exons 4-8, encompassing the RAS-binding domain. This variant exhibits enhanced dimerization in cells with low RAS activation, leading to resistance to RAF inhibitors. The mutation that abolishes dimerization of this variant restores sensitivity to the RAF inhibitor. The authors also found that BRAF(V600E) splicing variants lacking the RAS-binding domain were present in tumors of six out of 19 patients with acquired resistance to vemurafenib. This mechanism suggests that RAF inhibitors may be less effective in tumors with elevated RAS-GTP levels or increased RAF dimerization in the absence of RAS activation.The study identifies a novel mechanism of RAF inhibitor resistance in melanomas with mutant BRAF(V600E). Resistance is mediated by the expression of a 61kd variant form of BRAF(V600E) that lacks exons 4-8, encompassing the RAS-binding domain. This variant exhibits enhanced dimerization in cells with low RAS activation, leading to resistance to RAF inhibitors. The mutation that abolishes dimerization of this variant restores sensitivity to the RAF inhibitor. The authors also found that BRAF(V600E) splicing variants lacking the RAS-binding domain were present in tumors of six out of 19 patients with acquired resistance to vemurafenib. This mechanism suggests that RAF inhibitors may be less effective in tumors with elevated RAS-GTP levels or increased RAF dimerization in the absence of RAS activation.