# Melanoma: Pathogenesis and Targeted Therapy

## TL;DR

This review discusses the molecular causes of melanoma and current treatments, focusing on targeted therapies and immunotherapy for improved outcomes.

## Contribution

The paper provides a comprehensive review of recent advances and challenges in melanoma treatment, particularly for NRAS-mutant cases.

## Key findings

- BRAF–MEK inhibitor combinations are standard for BRAF-mutant melanoma.
- MEK inhibitors like tunlametinib show efficacy for NRAS-mutant melanoma.
- Immune checkpoint inhibitors have become a cornerstone therapy for advanced melanoma.

## Abstract

Melanoma is the most aggressive skin malignant tumor, typically exhibiting a high mutation burden and potentially harboring mutations in NRAS, BRAF, or NF1. To enhance survival rates, these driver alterations can achieve significant antitumor activity through targeted therapy. In the past decade, BRAF inhibitors combined with MEK inhibitors significantly improved the prognosis of BRAF mutation melanoma. Nevertheless, researchers have attempted various strategies to block the NRAS signaling pathway, NRAS mutation in melanoma is still considered to be untargetable. In recent years, MEK inhibitors like binimetinib and tunlametinib have displayed the efficacy for NRASmut melanoma, with tunlametinib being the first and only approved MEK inhibitor for advanced NRASmut melanoma. On the other hand, immune checkpoint inhibitors including PD‐1/PD‐L1 inhibitors and cytotoxic T‐lymphocyte antigen 4 （CTLA‐4） inhibitors changed the treatment landscape of advanced melanoma. In this review, we have summarized the current knowledge of molecular pathogenesis and classification of melanoma. Subsequently, we explored current and potential treatment approaches for melanoma, primarily encompassing BRAF inhibitors, MEK inhibitors, and immunotherapy, with a particular focus on their clinical relevance of development. Finally, the challenges in the treatment of melanoma, particularly in immunotherapy and targeted therapy, are summarized and discussed.

The treatment landscape for advanced melanoma has evolved significantly. BRAF–MEK inhibitor combinations are standard for BRAF‐mutant melanoma, whereas targeting NRAS mutations is more challenging, with MEK inhibitors like tunlametinib emerging as an option. Alongside these developments, immune checkpoint inhibitors have become a cornerstone therapy. This review summarizes the molecular classification of melanoma, synthesizes current therapeutic approaches including targeted and immunotherapy, and highlights persistent clinical challenges.