The study investigates the relationship between BRAF mutations and sensitivity to MEK inhibition in cancer cells. Using small-molecule MEK inhibitors and integrated genetic and pharmacologic analysis, the authors found that BRAF mutations are associated with enhanced and selective sensitivity to MEK inhibition compared to 'wild-type' cells or cells with RAS mutations. This sensitivity was observed regardless of tissue lineage and correlated with downregulation of cyclin D1 protein expression and G1 arrest. MEK inhibition completely abrogated tumor growth in BRAF mutant xenografts but only partially inhibited RAS mutant tumors. The findings suggest that BRAF mutant tumors have a critical dependency on MEK-ERK signaling, making them highly sensitive to pharmacological MEK inhibition. The study also highlights the potential therapeutic strategy of targeting MEK in BRAF mutant cancers.The study investigates the relationship between BRAF mutations and sensitivity to MEK inhibition in cancer cells. Using small-molecule MEK inhibitors and integrated genetic and pharmacologic analysis, the authors found that BRAF mutations are associated with enhanced and selective sensitivity to MEK inhibition compared to 'wild-type' cells or cells with RAS mutations. This sensitivity was observed regardless of tissue lineage and correlated with downregulation of cyclin D1 protein expression and G1 arrest. MEK inhibition completely abrogated tumor growth in BRAF mutant xenografts but only partially inhibited RAS mutant tumors. The findings suggest that BRAF mutant tumors have a critical dependency on MEK-ERK signaling, making them highly sensitive to pharmacological MEK inhibition. The study also highlights the potential therapeutic strategy of targeting MEK in BRAF mutant cancers.