A mutation-resolved therapeutic atlas of NRAS-mutant melanoma reveals genotype-selective response to RAS(ON) inhibition and adaptive STAT3 survival

NRAS-mutated melanoma remains a major unmet clinical need, with no approved targeted therapy and rapid progression on standard treatment. Tri-complex RAS(ON) inhibitors such as daraxonrasib (RMC-6236) and RMC-7977 have shown early clinical activity, but the mutation-specific sensitivity landscape and adaptive resistance programs in melanoma remain undefined. To address this, we generated an isogenic 3D melanoma platform and performed a saturation mutagenesis screen across 95 NRAS missense variants (>99% of clinically recurrent variants), profiling oncogenic fitness and responses to six RAS-targeting agents in spheroids and xenografts. RMC-6236 and RMC-7977 showed the broadest activity and stratified recurrent NRAS mutants into hypersensitive (G12 variants and Q61R/K/L; [~]95% of cases), moderately sensitive (G13D/R/V; [~]4%), and resistant (G60E and Q61P; [~]1%) classes. Structural analyses supported distinct mechanisms underlying reduced susceptibility in a restricted subset of variants. In sensitive genotypes, RAS(ON) inhibition elicited an adaptive cytokine- and RTK-associated survival program converging on STAT3. Co-inhibition of STAT3 enhanced apoptosis, suppressed MYC, and induced tumor regression in NRAS-mutant melanoma models. Together, these findings define a mutation-resolved therapeutic landscape for NRAS-mutant melanoma and identify adaptive STAT3 signaling as a rational target for combination therapy. Statement of Translational SignificanceNRAS-mutated melanoma lacks effective targeted treatments, and clinical responses to immunotherapy are suboptimal. This study presents the first comprehensive drug sensitivity map across 95 NRAS mutations in melanoma, identifying the pan-RAS(ON) inhibitors RMC-6236 and RMC-7977 as broadly effective agents. Multiple mutants with reduced susceptibility are identified, providing mutation-informed guidance for patient selection and clinical trial stratification. Mechanistic analyses reveal that RTK/cytokine-driven STAT3 activation functions as a key survival pathway under RAS(ON) blockade, and its inhibition markedly enhances the efficacy of pan-RAS(ON) inhibitors. These findings support mutation-guided use of RAS(ON) inhibition and highlight STAT3 co-targeting as a rational strategy to strengthen and prolong therapeutic responses in NRAS-mutated melanoma. Highlights- A functional and therapeutic atlas defines 95 recurrent and nonrecurrent NRAS missense variants in melanoma - RMC-6236 and RMC-7977 show broad but genotype-selective activity across major NRAS mutations - A restricted subset of recurrent NRAS mutants shows reduced susceptibility to RAS(ON) inhibition - RAS(ON) inhibition induces an adaptive STAT3 survival program that is therapeutically targetable