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

## TL;DR

This review explores how mutations in the MAPK pathway drive melanoma and how combination therapies may improve treatment outcomes.

## Contribution

The paper highlights novel combination strategies targeting multiple signaling axes in melanoma.

## Key findings

- BRAF/MEK inhibitors improve outcomes in BRAF-mutant melanoma but resistance remains a challenge.
- Combination therapies targeting MAPK and PI3K-AKT pathways show promise in overcoming resistance.
- Biomarker-guided approaches are critical for precision treatment in mutation-driven melanoma.

## Abstract

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.