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Pathway Description
Sorafenib Action Pathway
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Drug Action
Created: 2020-08-13
Last Updated: 2023-10-25
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
Capon DJ, Chen EY, Levinson AD, Seeburg PH, Goeddel DV: Complete nucleotide sequences of the T24 human bladder carcinoma oncogene and its normal homologue. Nature. 1983 Mar 3;302(5903):33-7. doi: 10.1038/302033a0.
Pubmed: 6298635
Reddy EP: Nucleotide sequence analysis of the T24 human bladder carcinoma oncogene. Science. 1983 Jun 3;220(4601):1061-3. doi: 10.1126/science.6844927.
Pubmed: 6844927
Sekiya T, Fushimi M, Hori H, Hirohashi S, Nishimura S, Sugimura T: Molecular cloning and the total nucleotide sequence of the human c-Ha-ras-1 gene activated in a melanoma from a Japanese patient. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4771-5. doi: 10.1073/pnas.81.15.4771.
Pubmed: 6087347
Giebel LB, Strunk KM, Holmes SA, Spritz RA: Organization and nucleotide sequence of the human KIT (mast/stem cell growth factor receptor) proto-oncogene. Oncogene. 1992 Nov;7(11):2207-17.
Pubmed: 1279499
Andre C, Hampe A, Lachaume P, Martin E, Wang XP, Manus V, Hu WX, Galibert F: Sequence analysis of two genomic regions containing the KIT and the FMS receptor tyrosine kinase genes. Genomics. 1997 Jan 15;39(2):216-26. doi: 10.1006/geno.1996.4482.
Pubmed: 9027509
Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessinger J, Francke U, Ullrich A: Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J. 1987 Nov;6(11):3341-51.
Pubmed: 2448137
Saha M, Carriere A, Cheerathodi M, Zhang X, Lavoie G, Rush J, Roux PP, Ballif BA: RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation. Biochem J. 2012 Oct 1;447(1):159-66. doi: 10.1042/BJ20120938.
Pubmed: 22827337
Hart TC, Zhang Y, Gorry MC, Hart PS, Cooper M, Marazita ML, Marks JM, Cortelli JR, Pallos D: A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1. Am J Hum Genet. 2002 Apr;70(4):943-54. doi: 10.1086/339689. Epub 2002 Feb 26.
Pubmed: 11868160
Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, Li L, Yassin Y, Tamburino AM, Neel BG, Kucherlapati RS: Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007 Jan;39(1):70-4. doi: 10.1038/ng1926. Epub 2006 Dec 3.
Pubmed: 17143285
Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J: The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992 Aug 7;70(3):431-42. doi: 10.1016/0092-8674(92)90167-b.
Pubmed: 1322798
Bochmann H, Gehrisch S, Jaross W: The gene structure of the human growth factor bound protein GRB2. Genomics. 1999 Mar 1;56(2):203-7. doi: 10.1006/geno.1998.5692.
Pubmed: 10051406
Skolnik EY, Lee CH, Batzer A, Vicentini LM, Zhou M, Daly R, Myers MJ Jr, Backer JM, Ullrich A, White MF, et al.: The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling. EMBO J. 1993 May;12(5):1929-36.
Pubmed: 8491186
Hong SW, Jin DH, Shin JS, Moon JH, Na YS, Jung KA, Kim SM, Kim JC, Kim KP, Hong YS, Lee JL, Choi EK, Lee JS, Kim TW: Ring finger protein 149 is an E3 ubiquitin ligase active on wild-type v-Raf murine sarcoma viral oncogene homolog B1 (BRAF). J Biol Chem. 2012 Jul 6;287(28):24017-25. doi: 10.1074/jbc.M111.319822. Epub 2012 May 24.
Pubmed: 22628551
Stephens RM, Sithanandam G, Copeland TD, Kaplan DR, Rapp UR, Morrison DK: 95-kilodalton B-Raf serine/threonine kinase: identification of the protein and its major autophosphorylation site. Mol Cell Biol. 1992 Sep;12(9):3733-42. doi: 10.1128/mcb.12.9.3733.
Pubmed: 1508179
Scherer SW, Cheung J, MacDonald JR, Osborne LR, Nakabayashi K, Herbrick JA, Carson AR, Parker-Katiraee L, Skaug J, Khaja R, Zhang J, Hudek AK, Li M, Haddad M, Duggan GE, Fernandez BA, Kanematsu E, Gentles S, Christopoulos CC, Choufani S, Kwasnicka D, Zheng XH, Lai Z, Nusskern D, Zhang Q, Gu Z, Lu F, Zeesman S, Nowaczyk MJ, Teshima I, Chitayat D, Shuman C, Weksberg R, Zackai EH, Grebe TA, Cox SR, Kirkpatrick SJ, Rahman N, Friedman JM, Heng HH, Pelicci PG, Lo-Coco F, Belloni E, Shaffer LG, Pober B, Morton CC, Gusella JF, Bruns GA, Korf BR, Quade BJ, Ligon AH, Ferguson H, Higgins AW, Leach NT, Herrick SR, Lemyre E, Farra CG, Kim HG, Summers AM, Gripp KW, Roberts W, Szatmari P, Winsor EJ, Grzeschik KH, Teebi A, Minassian BA, Kere J, Armengol L, Pujana MA, Estivill X, Wilson MD, Koop BF, Tosi S, Moore GE, Boright AP, Zlotorynski E, Kerem B, Kroisel PM, Petek E, Oscier DG, Mould SJ, Dohner H, Dohner K, Rommens JM, Vincent JB, Venter JC, Li PW, Mural RJ, Adams MD, Tsui LC: Human chromosome 7: DNA sequence and biology. Science. 2003 May 2;300(5620):767-72. doi: 10.1126/science.1083423. Epub 2003 Apr 10.
Pubmed: 12690205
Lee JE, Beck TW, Brennscheidt U, DeGennaro LJ, Rapp UR: The complete sequence and promoter activity of the human A-raf-1 gene (ARAF1). Genomics. 1994 Mar 1;20(1):43-55. doi: 10.1006/geno.1994.1125.
Pubmed: 8020955
Beck TW, Huleihel M, Gunnell M, Bonner TI, Rapp UR: The complete coding sequence of the human A-raf-1 oncogene and transforming activity of a human A-raf carrying retrovirus. Nucleic Acids Res. 1987 Jan 26;15(2):595-609. doi: 10.1093/nar/15.2.595.
Pubmed: 3029685
Yokoyama T, Takano K, Yoshida A, Katada F, Sun P, Takenawa T, Andoh T, Endo T: DA-Raf1, a competent intrinsic dominant-negative antagonist of the Ras-ERK pathway, is required for myogenic differentiation. J Cell Biol. 2007 Jun 4;177(5):781-93. doi: 10.1083/jcb.200703195. Epub 2007 May 29.
Pubmed: 17535970
Seger R, Seger D, Lozeman FJ, Ahn NG, Graves LM, Campbell JS, Ericsson L, Harrylock M, Jensen AM, Krebs EG: Human T-cell mitogen-activated protein kinase kinases are related to yeast signal transduction kinases. J Biol Chem. 1992 Dec 25;267(36):25628-31.
Pubmed: 1281467
Zheng CF, Guan KL: Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2. J Biol Chem. 1993 May 25;268(15):11435-9.
Pubmed: 8388392
Stewart S, Sundaram M, Zhang Y, Lee J, Han M, Guan KL: Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK localization. Mol Cell Biol. 1999 Aug;19(8):5523-34. doi: 10.1128/mcb.19.8.5523.
Pubmed: 10409742
Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. doi: 10.1101/gr.2596504.
Pubmed: 15489334
Mittal R, Peak-Chew SY, McMahon HT: Acetylation of MEK2 and I kappa B kinase (IKK) activation loop residues by YopJ inhibits signaling. Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18574-9. doi: 10.1073/pnas.0608995103. Epub 2006 Nov 20.
Pubmed: 17116858
Rosnet O, Buhring HJ, Marchetto S, Rappold I, Lavagna C, Sainty D, Arnoulet C, Chabannon C, Kanz L, Hannum C, Birnbaum D: Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia. 1996 Feb;10(2):238-48.
Pubmed: 8637232
Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H, Naoe T: Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia. 1998 Sep;12(9):1333-7.
Pubmed: 9737679
Rocnik JL, Okabe R, Yu JC, Lee BH, Giese N, Schenkein DP, Gilliland DG: Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD. Blood. 2006 Aug 15;108(4):1339-45. doi: 10.1182/blood-2005-11-011429. Epub 2006 Apr 20.
Pubmed: 16627759
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