Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration-approved targeted therapy in advanced melanoma

Sunilkumar Kakadia,1 Naveen Yarlagadda,1 Ramez Awad,2 Madappa Kundranda,3 Jiaxin Niu,3 Boris Naraev,3 Lida Mina,3 Tomislav Dragovich,3 Mark Gimbel,3 Fade Mahmoud3 1Department of Internal Medicine, Division of Hematology and Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 2Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 3TW Lewis Melanoma Center of Excellence, Banner MD Anderson Cancer Center, Gilbert, AZ, USA Abstract: Approximately 50% of melanomas harbor an activating BRAF mutation. Combined BRAF and MEK inhibitors such as dabrafenib and trametinib, vemurafenib and cobimetinib, and encorafenib and binimetinib are US Food and Drug Administration (FDA)-approved to treat patients with BRAFV600-mutated advanced melanoma. Both genetic and epigenetic alterations play a major role in resistance to BRAF inhibitors by reactivation of the MAPK and/or the PI3K–Akt pathways. The role of BRAF inhibitors in modulating the immunomicroenvironment and perhaps enhancing the efficacy of checkpoint inhibitors is gaining interest. This article provides a comprehensive review of mechanisms of resistance to BRAF and MEK inhibitors in melanoma and summarizes landmark trials that led to the FDA approval of BRAF and MEK inhibitors in metastatic melanoma. Keywords: malignant melanoma, targeted therapy, BRAF inhibitor, MEK inhibitor, resistance&nbsp