NRAS mutant melanoma: an overview for the clinician for melanoma management.

Melanoma is the deadliest form of skin cancer and the incidence continues to rise in the United States and worldwide. Activating mutations in RAS oncogenes are found in roughly a third of all human cancers. Mutations in NRAS occur in approximately a fifth of cutaneous melanomas and are associated with aggressive clinical behavior. Cells harboring oncogenic NRAS mutations exhibit activation of multiple signaling cascades, including PI3K/Akt, MEK-ERK and RAL, which collectively stimulate cancer growth. While strategies to target N-Ras itself have proven ineffective, targeting one or more N-Ras effector pathways has shown promise in preclinical models. Despite promising preclinical data, current therapies for NRAS mutant melanoma remain limited. Immune checkpoint inhibitors and targeted therapies for BRAF mutant melanoma are transforming the treatment of metastatic melanoma, but the ideal treatment for NRAS mutant melanoma remains unknown. Improved understanding of NRAS mutant melanoma and relevant N-Ras effector signaling modules will be essential to develop new treatment strategies.