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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
VOLUME: 11
ISSUE: 3
DOI: 10.2174/187152011795347469      Price:  $58









BRAF as a Target for Cancer Therapy

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Author(s): Rodrigo Dienstmann and Josep Tabernero
Pages 285-295 (11)
Abstract:
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.
Keywords:
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
Affiliation:
Medical Oncology Department, Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain.