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Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)
ISSN (Print): 1871-5206
ISSN (Online): 1875-5992
DOI: 10.2174/187152011795347469      Price:  $58

BRAF as a Target for Cancer Therapy

Author(s): Rodrigo Dienstmann and Josep Tabernero
Pages 285-295 (11)
Tumors with mutations in the gene encoding the serine-threonine protein kinase BRAF are dependent on the MAPK signaling pathway for their growth, what offers an opportunity to test oncogene-targeted therapy. Mutations at the position V600 of BRAF were described in approximately 8% of all solid tumors, including 50% of melanomas, 30 to 70% of papillary thyroid carcinomas and 5 to 8% of colorectal adenocarcinomas. Specific BRAF kinase inhibitors are undergoing rapid clinical development and promising data on efficacy have been demonstrated in activated mutant BRAF V600 melanomas. This review article will address: (a) preclinical data on the antitumor activity of BRAF inhibitors in cell lines/ in vivo models and their opposing functions as inhibitors or activators of the MAPK pathway, depending on the cellular context; (b) drug development from non-selective RAF inhibitors to selective BRAF inhibitors, such as PLX4032 and GSK2118436, with emphasis in the clinical efficacy and toxicity of these agents; and (c) possible mechanisms of resistance to BRAF inhibitors and strategies to overcome its development in BRAF mutant tumors.
BRAF V600, BRAF inhibitor, melanoma, RAF inhibitor, resistance, targeted therapy, ARAF, BRAF, MAPK kinase, C-terminal kinase domain, phosphatase, NRAS mutations, cytotoxic chemotherapy, hospho-ERK, PTEN
Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain.