title: Targeting oncogenic drivers and the immune system in melanoma.
abstract: Melanoma is one of the most common cancers in Western countries but has defied the trend of reductions in age-adjusted mortality observed in most other cancers in recent years. Biologically, melanoma is characterized by a high propensity to metastasize at low tumor volumes necessitating the need for effective drug therapies to support efforts in prevention and early detection for reducing mortality. Efforts to study the clinical biology of melanoma have led to a new understanding of the disease, with genomic studies identifying several targetable oncogenes, in particular the protein kinases BRAF and KIT. Biologic studies have also identified a variety of immunologic targets, including the programmed death 1 (PD-1) and cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4) inhibitory molecules expressed on T lymphocytes. After several decades of clinical trials that failed to demonstrate improvement in overall survival in patients with advanced melanoma, small molecule inhibitors of BRAF or MEK and inhibition of CTLA-4 can improve survival in patients with advanced disease. These early clinical studies have provided a great opportunity to improve mortality in melanoma with the significant potential of combinations of signaling inhibitors or signaling inhibitors combined with immunologic agents, particularly when used in the adjuvant setting, and to transform the care of patients with this most challenging of cancers.
authors.affiliation: Division of Cancer Medicine and Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. grant.mcarthur@petermac.org
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
mesh_terms: D019264:Adoptive Transfer; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases