title: Molecular pathways: targeting NRAS in melanoma and acute myelogenous leukemia.
abstract: Successful targeting of specific oncogenic "driver" mutations with small-molecule inhibitors has represented a major advance in cancer therapeutics over the past 10 to 15 years. The most common activating oncogene in human malignancy, RAS (rat sarcoma), has proved to be an elusive target. Activating mutations in RAS induce mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase-AKT pathway signaling and drive malignant progression in up to 30% of cancers. Oncogenic NRAS mutations occur in several cancer types, notably melanoma, acute myelogenous leukemia (AML), and less commonly, colon adenocarcinoma, thyroid carcinoma, and other hematologic malignancies. Although NRAS-mutant tumors have been recalcitrant to targeted therapeutic strategies historically, newer agents targeting MAP/ERK kinase 1 (MEK1)/2 have recently shown signs of clinical efficacy as monotherapy. Combination strategies of MEK inhibitors with other targeted agents have strong preclinical support and are being evaluated in clinical trials. This review discusses the recent preclinical and clinical studies about the role of NRAS in cancer, with a focus on melanoma and AML.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; and douglas.b.johnson@vanderbilt.edu.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Johnson
authors.affiliation: Departments of Molecular Oncology and Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida.
authors.forename: Keiran S M
authors.initials: KS
authors.lastname: Smalley
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D058990:Molecular Targeted Therapy; D011379:Prognosis; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human