Kanser tedavisinde mTOR sinyal yolağı ve mTOR inhibitörleri

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.

mTOR signaling pathway and mTOR inhibitors in the treatment of cancer

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 mito- gen-activated protein kinase (MAPK)/Ras signalling cas- cades. mTOR has been defined as a key kinase acting downstream of the activation of PI3K/AKT. These path- ways are frequently deteriorated in cancer, and therefore mTOR inhibition is a important antitumor target. mTOR inhibitors include rapamycin (i.e. sirolimus) and its deriva- tives; temsirolimus, everolimus, ridaforolimus and defo- rolimus. mTOR inhibitors has the important potential to provide anticancer activity in many tumor types.

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1. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev 2006;5:671- 8.
2. 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.
3. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004;18:1926-5.
4. Douros J, Suffnes M. New antitumor substances of natural origin. Cancer Treat Rev 1981; 8:63-7.
5. 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.
6. 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.
7. 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.
8. Wysocki PJ. mTOR in renal cell cancer: modulator of tu- mor biology and therapeutic target. Expert Rev Mol Diagn 2009;9: 231-41.
9. Shaw RJ, Cantley LC. Ras, PI(3)K, and mTOR signalling controls tumor cell growth. Nature 2006; 441:424-30.
10. Vivanco I, Sawyers CL, The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2: 489-01.
11. 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.
12. Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 2005;8:179-3.
13. Pawson T. Introduction: Protein kinases. FASEB J 1994;8:1112-13.
14. 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.
15. Figlin RA, Brown E, Armstrong AJ, et al. NCCN task force report: mTOR inhibition in solid tumors. JNCCN 2008; 6:1-20.
16. Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098-01.
17. Zhou H, Huang S. mTOR signaling in cancer cell motility and tumor metastasis. Crit Rev Eukaryot Gene Expr 2010; 20: 1-16.
18. 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.
19. 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.
20. Thomas G, Hall MN. TOR signaling and control of control of cell growth. Curr Opin Cell Biol 1997; 9: 782-7.
21. Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000;103:253-2.
22. 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.
23. 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.
24. 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.
25. Yekaterina Y. Zaytseva, Joseph D. Valentino, Pat Gulhati, B. Mark Evers. mTOR inhibitors in cancer therapy. Cancer Letters 2012:319:1-7.