MAP2K1 and melanoma: RAF inhibition resistance. Off-target MAPK vertical pathway alterations account for 52% BRAFi resistance in 71 melanoma patients, including NRAS mutations (G12D/R, G13R, and Q61K/R/L) at 18%, KRAS mutations (G12C, G12R, and Q61H) at 7% and MAP2K1 mutations at 3% (K57N and C121S) 80.