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 in patients with NRAS mutant melanoma is poor, and effective targeted treatment strategies are still lacking. Mutant NRAS mainly acts by activating RAF–MEK–ERK signalling to promote carcinogenesis in melanoma. In recent years, significant clinical advances have been made in targeting the NRAS–MAPK (mitogen-activated protein kinase) pathway, with novel therapies such as the MEK inhibitor tunlametinib and a combination therapy of the pan-RAF inhibitor naporafenib + trametinib leading the way. In this review, we systematically summarize the recent advances made 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 immunotherapy, to treat NRAS mutant melanoma. Additionally, we discuss the current issues and emerging countermeasures related to targeted therapy for NRAS mutant melanoma.