title: Emerging insights into resistance to BRAF inhibitors in melanoma.
abstract: Melanoma is the most aggressive form of skin cancer. The treatment of patients with advanced melanoma is rapidly evolving due to an improved understanding of molecular drivers of this disease. Somatic mutations in BRAF are the most common genetic alteration found in these tumors. Recently, two different mutant-selective small molecule inhibitors of BRAF, vemurafenib and dabrafenib, have gained regulatory approval based on positive results in randomized phase III trials. While the development of these agents represents a landmark in the treatment of melanoma, the benefit of these agents is limited by the frequent and rapid onset of resistance. The identification of several molecular mechanisms of resistance to BRAF inhibitors is rapidly leading to the clinical testing of combinatorial strategies to improve the clinical benefit of these agents. These mechanisms, and the lessons learned from the initial testing of the BRAF inhibitors, provide multiple insights that may facilitate the development of targeted therapies against other oncogenic mutations in melanoma, as well as in other cancers.
authors.affiliation: Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.
authors.forename: Amanda D
authors.initials: AD
authors.lastname: Bucheit
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States. Electronic address: MDavies@mdanderson.org.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF inhibitor; MAPK; Melanoma; PI3K; Resistance