TY - JOUR T1 - Kanser tedavisinde mTOR sinyal yolağı ve mTOR inhibitörleri TT - mTOR signaling pathway and mTOR inhibitors in the treatment of cancer AU - Küçüköner, Mehmet PY - 2013 DA - March DO - 10.5798/diclemedj.0921.2013.01.0248 JF - Dicle Medical Journal JO - diclemedj PB - Dicle University WT - DergiPark SN - 1300-2945 SP - 156 EP - 160 VL - 40 IS - 1 LA - tr AB - mTOR (Rapamisin protein kompleksinin memeli hedefi) hücre büyümesi ve metabolizmasında önemli role sahip­tir. Kanserde önemli olduğu saptanan üç temel sinyalizas­yon yolu; (PI3K)/AKT kinaz zinciri, protein kinaz C ailesi (PKC) ve mitojenle aktive olan protein kinaz (MAPK)/Ras vardır. mTOR; PI3K/AKT sinyal yolağının akış aşağı akti­vasyonunda anahtar bir kinazdır. Bu yolaklar sıklıkla kan­serde bozulur ve bu yüzden de mTOR önemli bir antitü­mör hedeftir. Antikanser ajanlar olarak mTOR inhibitörleri rapamisin ve ondan türetilmiş temsirolimus, everolimus ve ridaforolimus sonradan deforolimus oluşturmaktadır. mTOR inhibitörleri birçok kanser tipinde önemli bir hedef­tir. KW - PI3K/AKT/mTOR KW - mTOR inhibitörle­ri KW - kanser N2 - Mammalian target of rapamycin (mTOR) plays a major role in the regulation of protein translation, cell growth, and metabolism. Three basic signalling pathways that have been described as important in cancer including the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR kinase cascade, the protein kinase C (PKC) family, and the mito­gen-activated protein kinase (MAPK)/Ras signalling cas­cades. mTOR has been defined as a key kinase acting downstream of the activation of PI3K/AKT. These path­ways are frequently deteriorated in cancer, and therefore mTOR inhibition is a important antitumor target. mTOR inhibitors include rapamycin (i.e. sirolimus) and its deriva­tives; temsirolimus, everolimus, ridaforolimus and defo­rolimus. mTOR inhibitors has the important potential to provide anticancer activity in many tumor types. CR - Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev 2006;5:671- 8. CR - Seghal SN, Baker H, Vézina C. Rapamycin (AY-22,989), a new antifungal antiobiotic II. Fermentation, isolation and characterization. J Antibiot 1975; 28:727-2. CR - Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004;18:1926-5. CR - Douros J, Suffnes M. New antitumor substances of natural origin. Cancer Treat Rev 1981; 8:63-7. CR - Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of sirolimus kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004;22:909-8. CR - Motzer RJ, Escudier B, Oudard S, et al. RAD001 vs placebo in patients with metastatic renal cell carcinoma after pro- gression on VEGFr-TKI therapy: results from a random- ized, double blind, multicenter phase-III study [abstract]. J Clin Oncol 2008;26:Abstract LBA5026. CR - Yuan R, Kay A, Berg WJ and Lebwohl D. Targeting tumori- genesis: development and use of mTOR inhibitors in cancer therapy. J Hematol & Oncol 2009; 2:1-12. CR - Wysocki PJ. mTOR in renal cell cancer: modulator of tu- mor biology and therapeutic target. Expert Rev Mol Diagn 2009;9: 231-41. CR - Shaw RJ, Cantley LC. Ras, PI(3)K, and mTOR signalling controls tumor cell growth. Nature 2006; 441:424-30. CR - Vivanco I, Sawyers CL, The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2: 489-01. CR - Bellacosa A, Chan TO, Ahmed NN, et al.Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene 1998;17: 313-25. CR - Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 2005;8:179-3. CR - Pawson T. Introduction: Protein kinases. FASEB J 1994;8:1112-13. CR - Sancak Y, Thoreen CC, Peterson TR et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 2007;25: 903-15. CR - Figlin RA, Brown E, Armstrong AJ, et al. NCCN task force report: mTOR inhibition in solid tumors. JNCCN 2008; 6:1-20. CR - Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098-01. CR - Zhou H, Huang S. mTOR signaling in cancer cell motility and tumor metastasis. Crit Rev Eukaryot Gene Expr 2010; 20: 1-16. CR - Toschi A, Lee E, Gadir N, Ohh M, Foster DA. Differen- tial dependence of hypoxia- inducible factors 1a and 2a on mTORC1 and mTORC2. J. Biol Chem 2008;283:34495-9. CR - Feng, Z, Zhang, H, Levine, AJ, Jin S. The coordinate regu- lation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci 2005;102: 8204-9. CR - Thomas G, Hall MN. TOR signaling and control of control of cell growth. Curr Opin Cell Biol 1997; 9: 782-7. CR - Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000;103:253-2. CR - Motzer RJ, Escudier B, Oudard S, et al. RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell car- cinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449-56. CR - Yao JC, Phan AT, Chang DZ etal. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low to inter- mediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 2008;26:4311-18. CR - www.clinicaltrials.gov: Ridaforolimus in treatment of sar- coma - SUCCEED (Sarcoma Multi-Center Clinical Evalu- ation of the Efficacy of Ridaforolimus). (http://www.clini- caltrials.gov/ct2/ show/study/NCT00538239). Accessed Feb 19, 2012. CR - Yekaterina Y. Zaytseva, Joseph D. Valentino, Pat Gulhati, B. Mark Evers. mTOR inhibitors in cancer therapy. Cancer Letters 2012:319:1-7. UR - https://doi.org/10.5798/diclemedj.0921.2013.01.0248 L1 - https://dergipark.org.tr/en/download/article-file/54518 ER -