title: Treatment of NRAS-mutant melanoma.
abstract: NRAS mutations in codons 12, 13, and 61 arise in 15-20 % of all melanomas. These alterations have been associated with aggressive clinical behavior and a poor prognosis. Until recently, there has been a paucity of promising genetically targeted therapy approaches for NRAS-mutant melanoma (and RAS-mutant malignancies in general). MEK inhibitors, particularly binimetinib, have shown activity in this cohort. Based on pre-clinical and early clinical studies, combining MEK inhibitors with agents inhibiting the cell cycling and the PI3K-AKT pathway appears to provide additional benefit. In particular, a strategy of MEK inhibition and CDK4/6 inhibition is likely to be a viable treatment option in the future, and is the most promising genetically targeted treatment strategy for NRAS-mutant melanoma developed to date. In addition, immune-based therapies have shown increasing activity in advanced melanoma and may be particularly effective in those with NRAS mutations. Combination strategies of immune and targeted therapies may also play a role in the future although clinical trials testing these approaches are in early stages.
authors: Department of Medicine, Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 777 Preston Research Building, 2220 Pierce Avenue, Nashville, TN, 37232, USA, douglas.b.johnson@vanderbilt.edu.
authors: Douglas B
authors: DB
authors: Johnson
authors: Igor
authors: I
authors: Puzanov
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D007167:Immunotherapy; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation
chemical_list: D000970:Antineoplastic Agents; D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human