title: Resistance to BRAF-targeted therapy in melanoma.
abstract: BRAF mutations are identified in 40-50% of patients with melanoma. Treatment of these patients with either of two BRAF inhibitors (vemurafenib, dabrafenib) or the MEK inhibitor trametinib is associated with improved clinical benefit (response rate, progression free survival, and overall survival) compared with treatment with chemotherapy in three phase III trials. Unfortunately, most patients, including those who experience initial, profound tumour regression, have evidence of disease progression within 6-8 months after commencing therapy with one of these agents. The mechanisms of resistance are varied and include activation of alternative signalling pathways as well as reactivating the MAP kinase pathway through alternative means. This review describes relevant aspects of MAP kinase pathway signalling, summarises the clinical data with BRAF and MEK inhibitors, presents the known resistance mechanisms to BRAF inhibitor therapy, and provides some strategies for how resistance may be overcome.
authors.affiliation: Center for Melanoma Massachusetts General Hospital Cancer Center 55 Fruit Street, Boston, MA 02114, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Sullivan
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
mesh_terms: D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D010091:Oximes / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D011728:Pyridones / Q000627:therapeutic use; D011744:Pyrimidinones / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib