Targeting the MAPK Pathway for NRAS Mutant Melanoma: From Mechanism to Clinic

Abstract Mutant NRAS is the second-most common type of mutation in melanoma. The prognosis is poor in the patients with NRAS mutant melanoma, and effective targeted treatment strategies are still lacking. Mutant NRAS mainly acts through activating the RAF-MEK-ERK signaling to promote the carcinogenesis in melanoma. In recent years, significant clinical advancements have been achieved by targeting the NRAS-MAPK pathway, with novel therapies such as the MEK inhibitor tunlametinib and the combination therapy of the pan-RAF inhibitor naporafenib with trametinib leading the way. In this review, we will systematically summarize the recent advances in the direct targeting of mutant NRAS proteins and their downstream RAF and MEK proteins, as well as targeting the MAPK pathway in combination with other therapeutic targets, including the immunotherapy, to treat NRAS mutant melanoma. Additionally, we will further discuss the current issues and emerging countermeasures related to targeted therapy for NRAS mutant melanoma.