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Pathway Description
Sorafenib Action Pathway
Homo sapiens
Drug Action Pathway
Sorafenib, marketed as Nexavar, is a drug for the treatment of advanced renal cell carcinoma (primary kidney cancer). It is an inhibitor of the RAF kinase protein and cell surface kinases PDGF-beta receptor, VEGF 2 and 3 receptor (many sources also say VEGFR 1), c-KIT receptor, and FLT-3 receptor. Overall, sorafenib targets the Raf/Mek/Erk pathway. The kinases that are targeting are involved in angiogenesis which reduces blood flow to the tumor and also for genetic transcription for cell proliferation and replication. Sorafenib's mechanism of action works by inhibiting the cell surface kinases, which blocks their signalling to RAF and AKT pathways which are responsible for cell proliferation. C-KIT and FLT-3 on tumor cells are inhibited causing their proliferation to stop and the PDGF and VEGF receptors on endothelial cells are inhibited to stop the growth of new blood vessels that bring blood flow to the tumor. Sorafenib also inhibits RAF1 which is a protein that regulates apoptosis of the cell. With RAF1 blocked, apoptosis is not regulated and can occur. Sorafenib is taken orally in a tablet for and enters the bloodstream through the GI tract to be delivered to the site of action.
References
Sorafenib Pathway References
Li J, Yang Z, Tuo B. Role of OCT1 in hepatocellular carcinoma. Onco Targets Ther 12: 6013-6022, 2019.
Cusabio. MAPK signalling pathway. Cusabio. Retrevied from: https://www.cusabio.com/pathway/MAPK-signaling-pathway.html
Coventon J. A review of the mechanism of action and clinical applications of sorafenib in advanced osteosarcoma. Journal of Bone Oncology 8: 4-7, 2017.
Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie S, Wilhelm S, Lynch M, Carter C. Sorafenib Blocks the RAF/MEK/ERK Pathway, Inhibits Tumor Angiogenesis, and Induces Tumor Cell Apoptosis in Hepatocellular Carcinoma Model PLC/PRF/5. Cancer Research 66(24): 11851-11858, 2006.
Lyver R, Fetterly G, Lugade A, Thanavala Y. Sorafenib: a clinical and pharmacologic review. Expert Opinion on Pharmacotherapy 11(11): 1943-1955, 2010.
Cervello M, Bachvarov D, Lampiasi N, Cusimano A, Azzolina A, McCubrey J. A, Montalto G. Molecular mechanisms of sorafenib action in liver cancer cells. Cell Cycle 11(15): 2843-2855, 2012.
Zhu A. X. Development of sorafenib and other molecularly targeted agents in hepatocellular carcinoma. ACS Journals 112(2): 250-259, 2008.
Rini B. I. Vascular Endothelial Growth Factor–Targeted Therapy in Renal Cell Carcinoma: Current Status and Future Directions. Clinical Cancer Research 13(4): 1098-1106, 2007.
Koch S, Claesson-Welsh L. Signal Transduction by Vascular Endothelial Growth Factor Receptors. Cold Spring Harb Perspect Med. 2(7): 1-21, 2012.
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
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