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. © 2011 Bentham Science Publishers Ltd.
Original language | English |
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Pages (from-to) | 285-295 |
Journal | Anti-Cancer Agents in Medicinal Chemistry |
Volume | 11 |
Issue number | 3 |
DOIs | |
Publication status | Published - 1 Jan 2011 |
Keywords
- BRAF inhibitor
- BRAF V600
- Melanoma
- RAF inhibitor
- Resistance
- Targeted therapy