Dissecting the MAPK signaling landscape in malignant melanoma: from BRAF and NRAS mutations to precision combination therapies

Malignant melanoma is an aggressive skin malignancy with a complex molecular landscape and limited treatment durability in advanced stages. Aberrations in the MAPK pathway-most notably BRAF and NRAS mutations-have catalyzed the development of targeted therapies, particularly BRAF/MEK inhibitors, which have transformed outcomes in BRAF-mutant melanoma. However, resistance remains prevalent, driven by MAPK reactivation, epigenetic rewiring, and tumor microenvironmental feedback. In NRAS-mutant subtypes, MEK inhibition, CDK4/6 blockade, and immune checkpoint inhibition offer partial efficacy, yet monotherapies fail to achieve sustained responses. Emerging strategies focus on combinatorial regimens targeting RAF-MEK-ERK and PI3K-AKT axes, alongside immunotherapeutic integration. Rarer alterations in KIT and RTKs also define actionable subsets. This review synthesizes recent mechanistic insights and therapeutic advances in mutation-driven melanoma, highlighting the promise of biomarker-guided combination strategies and signaling crosstalk disruption as the next frontier in precision oncology.