ReviewsTargeting Mutant BRAF in Melanoma Current Status and Future Development of Combination Therapy StrategiesKudchadkar, Ragini MD*; Paraiso, Kim H.T. MS†‡; Smalley, Keiran S.M. PhD*†‡ Author Information From the Departments of *Cutaneous Oncology and †Molecular Oncology and ‡The Comprehensive Melanoma Research Center, The Moffitt Cancer Center, Tampa, FL. Conflicts of Interest and Source of Funding: Dr Keiran S.M. Smalley is currently receiving grants U54 CA143970-01 and R01 CA161107-01 from the National Institutes of Health, The Harry Lloyd Trust, and the State of Florida (09BN-14). For the remaining authors, none were declared. Reprints: Keiran S.M. Smalley, PhD, The Comprehensive Melanoma Research Center, The Moffitt Cancer Center, 12902 Magnolia Dr, Tampa, FL 33612. E-mail: [email protected]. The Cancer Journal: March/April 2012 - Volume 18 - Issue 2 - p 124-131 doi: 10.1097/PPO.0b013e31824b436e Buy Metrics Abstract The discovery of activating BRAF mutations in ∼50% of all melanomas has proved to be a turning point in the therapeutic management of the disseminated disease. In this commentary, we review the latest research delineating the role of mutant BRAF in melanoma initiation and progression and discuss the remarkable 10-year journey leading up to the recent U.S. Food and Drug Administration approval of the small-molecule BRAF inhibitor vemurafenib. We further outline the most recent findings on the mechanisms that underlie intrinsic and acquired BRAF inhibitor resistance and describe ongoing preclinical and clinical studies designed to delay or abrogate the onset of therapeutic escape. It is hoped that our evolving understanding of melanoma genetics and intracellular signaling coupled with a growing armamentarium of signal transduction inhibitors will lead to significant improvements in the level and durability of therapeutic response in metastatic melanoma. Copyright © 2012 Wolters Kluwer Health, Inc. All rights reserved.