title: Targeting NRAS in melanoma.
abstract: Cutaneous melanomas have mutations in the NRAS GTPase in 15% of cases. Compared to melanomas with BRAF mutations, or melanomas "wild-type" for BRAF and NRAS, melanomas with NRAS mutations are more likely to be thicker tumors and to have a higher mitotic rate. Preclinical studies indicate that melanoma cells with NRAS mutations are dependent on NRAS for survival and proliferation, making NRAS an attractive therapeutic target in melanoma. However, to date, therapeutic strategies for NRAS mutant melanomas have not been realized. Promising strategies to target NRAS include targeting the membrane localization of NRAS or reducing expression through the use of therapeutic small interfering RNAs. Finally, use of inhibitors to target downstream signaling through mitogen-activated protein kinase kinase and phosphatidylinositol 3-OH kinase or AKT are now entering clinical trials, and if these combinations can be safely delivered at sufficient dose to inhibit the targets, there is significant potential to target NRAS mutant melanoma.
authors.affiliation: Division of Cancer Medicine, Peter MacCallum Cancer Centre, Victoria, Australia.
authors.forename: Fergal C
authors.initials: FC
authors.lastname: Kelleher
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
mesh_terms: D000818:Animals; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D058990:Molecular Targeted Therapy; D009154:Mutation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)