Insights into RAS-driven melanoma and its therapeutic implications

NRAS mutations are present in 15-25 % of cutaneous melanomas, predominantly affecting codon 61 (Q61R > Q61K). Mutations at codons 12 and 13 are rare although they appear to be relatively enriched in mucosal subtype. KRAS alterations, while rare in cutaneous melanomas, are more frequently observed in melanoma brain metastases as well as in acral and mucosal subtypes, where NRAS mutations are less prevalent. For advanced RAS-mutant melanoma, systemic therapy currently relies on anti-PD-1-based immune checkpoint inhibition. MEK inhibitors have demonstrated only modest clinical benefit due to the development of resistance and are not approved outside of China for this subtype. Ongoing combination strategies include MEK inhibition with type II RAF inhibitors (naporafenib plus trametinib in phase III trial), ERK1/2 or ERK5 inhibitors, PI3K/mTOR pathway blockade, or CDK4/6 inhibition. Additional investigational approaches include mutation-specific RAS inhibitors (G12C inhibitors already approved for other cancers), NRAS-specific or pan-RAS inhibitors (daraxonrasib in phase III trial for other cancers), targeted protein degradation, RAS-directed peptide and mRNA vaccines (mRNA-4157). NRAS Q61K-derived neoepitopes bound to HLA-A*01:01 have been recognized as immunogenic, suggesting that mutation-specific immunotherapies could represent a promising future strategy. In conclusion, the advent of promising and emerging therapies is set to transform the management of RAS-driven melanoma, making a personalized, biomarker-informed treatment strategy essential for optimizing patient outcomes.