Raf kinase as a target for anticancer therapeutics.
The 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.
Sridhar
Srikala S
SS
Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Avenue, Suite 5-210, Toronto, Ontario, Canada M5G 2M9.
Hedley
David
D
Siu
Lillian L
LL
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001557:Benzenesulfonates / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D009536:Niacinamide / Q000031:analogs & derivatives; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010671:Phenylurea Compounds; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D000077157:Sorafenib; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; D010671:Phenylurea Compounds; D011725:Pyridines; C084881:flt3 ligand protein; D009536:Niacinamide; D000077157:Sorafenib; D019009:Proto-Oncogene Proteins c-kit; D040301:Vascular Endothelial Growth Factor Receptor-2; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases