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Raf kinase as a target for anticancer therapeutics Sridhar SS; Hedley D; Siu LLMol Cancer Ther 2005[Apr]; 4 (4): 677-85The Ras-Raf-MEK-ERK (ERK) pathway is a logical therapeutic target because it represents a common downstream pathway for several key growth factor tyrosine kinase receptors which are often mutated or overexpressed in human cancers. Although considered mainly growth-promoting, in certain contexts, this pathway also seems to be apoptosis-suppressing. Several novel agents targeting this pathway have now been developed and are in clinical trials. One of the most interesting new agents is BAY 43-9006. Although initially developed as a Raf kinase inhibitor, it can also target several other important tyrosine kinases including VEGFR-2, Flt-3, and c-Kit, which contributes to its antiproliferative and antiangiogenic properties. To date, encouraging results have been seen with BAY 43-9006, particularly in renal cell cancers which are highly vascular tumors. This review will provide an overview of the ERK signaling pathway in normal and neoplastic tissue, with a specific focus on novel therapies targeting the ERK pathway at the level of Raf kinase.|Animals[MESH]|Antineoplastic Agents/*pharmacology[MESH]|Apoptosis[MESH]|Benzenesulfonates/pharmacology[MESH]|Carcinoma, Renal Cell/metabolism[MESH]|Cell Line, Tumor[MESH]|Cell Proliferation[MESH]|Enzyme Activation[MESH]|Enzyme Inhibitors/*pharmacology[MESH]|Extracellular Signal-Regulated MAP Kinases/metabolism[MESH]|Humans[MESH]|Membrane Proteins/metabolism[MESH]|Models, Biological[MESH]|Neovascularization, Pathologic[MESH]|Niacinamide/analogs & derivatives[MESH]|Oligonucleotides, Antisense/pharmacology[MESH]|Phenylurea Compounds[MESH]|Phosphorylation[MESH]|Protein Structure, Tertiary[MESH]|Proto-Oncogene Proteins c-kit/metabolism[MESH]|Proto-Oncogene Proteins c-raf/*metabolism[MESH]|Pyridines/pharmacology[MESH]|Signal Transduction[MESH]|Sorafenib[MESH]|Time Factors[MESH]|Vascular Endothelial Growth Factor Receptor-2/metabolism[MESH] |
