title: B-Raf Inhibition in the Clinic: Present and Future.
abstract: Somatic activating mutations in the B-Raf kinase (BRAF mutations) are present in hairy-cell leukemia, cutaneous melanoma, thyroid carcinomas and, less commonly, in ovarian, colon, lung, and other malignancies. These mutations-in particular the most common substitution, V600E-are oncogenic drivers and important therapeutic targets. The development of small-molecule Raf inhibitors allowed rapid translation of basic advances to the clinic. In BRAF-mutant melanomas, orally bioavailable B-Raf inhibitors, such as vemurafenib, achieve dramatic responses initially, but this is followed by rapid emergence of resistance driven by numerous mechanisms and requiring second-generation treatment approaches. In tumors with wild-type B-Raf, vemurafenib paradoxically activates downstream signaling and cell proliferation and is thus contraindicated, highlighting again the importance of genotype-based clinical decision making. These advances were greatly facilitated by the study of biopsied tumor tissue, especially at the time of drug resistance. Combinatorial approaches targeting the Raf pathway hold promise for even more substantial clinical benefits in the future.
authors.affiliation: Department of Medicine; Department of Molecular and Cellular Biology; Dan L. Duncan Cancer Center; and Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030; email: mitsiade@bcm.edu.
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.affiliation: Department of Medicine; Department of Molecular and Cellular Biology; Dan L. Duncan Cancer Center; and Center for Drug Discovery, Baylor College of Medicine, Houston, Texas 77030; email: mitsiade@bcm.edu.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; 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*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010091:Oximes / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000077157:Sorafenib; D013449:Sulfonamides / Q000627:therapeutic use*; D013964:Thyroid Neoplasms / Q000188:drug therapy*; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D009536:Niacinamide; D000077157:Sorafenib; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; C561627:dabrafenib
keywords: colon cancer; dabrafenib; melanoma; thyroid cancer; trametinib; vemurafenib