Skip to main content
SpringerLink
Log in

mTOR

Properties and Therapeutics

  • Chapter
Molecular Targeting in Oncology

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

  • 1494 Accesses

Summary

The mammalian target of rapamycin (mTOR) is a serine threonine kinase that regulates cell growth in response to growth factor-mediated activation of receptor tyrosine kinase signaling or to cellular stresses such as the deprivation of nutrients, energy, or oxygen (hypoxia). A number of proteins responsible for both the activation and inhibition of mTOR, as well as some targets of mTOR kinase activity, are modified in cancer. The growth of a number of tumor cell lines is inhibited by treatment with rapamycin, the naturally occurring specific inhibitor of mTOR function. A role for mTOR in angiogenesis has also been proposed. These observations have resulted in the development of additional small molecule inhibitors directed against mTOR and the initiation of a number of clinical trials to evaluate the therapeutic potential of these compounds. Initial studies indicate these compounds may have some benefit for certain subsets of cancer. However, progress in predicting which patients will benefit has been hampered somewhat by trial design as well as an incomplete understanding of mTOR function and regulation. All of the current inhibitors of mTOR are close derivatives of rapamycin and inhibit mTOR using the same mechanism. The potential for development of alternatives to the current generation of mTOR inhibitors depends in part on the results of a number of current clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Cafferkey R, McLaughlin MM, Young PR, Johnson RK, Livi GP. Yeast TOR (DRR) proteins: amino-acid sequence alignment and identification of structural motifs. Gene 1994;141:133–136

    Article  PubMed  CAS  Google Scholar 

  2. Helliwell SB, Wagner P, Kunz J, Deuter-Reinhard M, Henriquez R, HallMN. TOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast. Mol Biol Cell 1994;5:105–118.

    PubMed  CAS  Google Scholar 

  3. Zheng XF, Florentino D, Chen J, Crabtree GR, Schreiber SL. TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell 1995;82:121–130.

    Article  PubMed  CAS  Google Scholar 

  4. Schmidt A, Kunz J, Hall MN. TOR2 is required for organization of the actin cytoskeleton in yeast. Proc Natl Acad Sci USA 1996;93:13780–13785.

    Article  PubMed  CAS  Google Scholar 

  5. Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004;6:1122–1128.

    Article  PubMed  CAS  Google Scholar 

  6. Sarbassov DD, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004;14:1296–1302.

    Article  PubMed  CAS  Google Scholar 

  7. Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 1994;369:756–758.

    Article  PubMed  CAS  Google Scholar 

  8. Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH. Raft1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 1994;78:35–43.

    Article  PubMed  CAS  Google Scholar 

  9. Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, Abraham RT. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 1995;270:815–822.

    Article  PubMed  CAS  Google Scholar 

  10. Chen Y, et al A putative sirolimus (rapamycin) effector protein. Biochem Biophys Res Commun 1994;203:1–7.

    Article  PubMed  CAS  Google Scholar 

  11. Abraham RT. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 2001;15:2177–2196.

    Article  PubMed  CAS  Google Scholar 

  12. Andrade MA, Bork P. HEAT repeats in the Huntington’s disease protein. Nat Genet 1995; 11:115–116.

    Article  PubMed  CAS  Google Scholar 

  13. Bosotti R, Isacchi A, Sonnhammer EL. FAT: a novel domain in PIK-related kinases. Trends Biochem Sci 2000;25:225–227.

    Article  PubMed  CAS  Google Scholar 

  14. Chen J, Zheng XF, Brown EJ, Schreiber SL. Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue. Proc Natl Acad Sci USA 1995;92:4947–4951.

    Article  PubMed  CAS  Google Scholar 

  15. Choi J, Chen J, Schreiber SL, Clardy J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 1996;273:239–242.

    Article  PubMed  CAS  Google Scholar 

  16. Scott PH, Brunn GJ, Kohn AD, Roth RA, Lawrence JC. Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc Natl Acad Sci USA 1998;95:7772–7777.

    Article  PubMed  CAS  Google Scholar 

  17. Nave B, Ouwens M, Withers DJ, Alessi DR, Shepherd PR. Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino acid deficiency on protein translation. Biochem J 1999;344:427–431.

    Article  PubMed  CAS  Google Scholar 

  18. Sekulic A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, Abraham RT. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin (mTOR) in mitogen-stimulated and transformed cells. Cancer Res 2000;60:3504–3513.

    PubMed  CAS  Google Scholar 

  19. Chung J, Grammer TC, Lemon KP, Kazlauskas A, Blenis J. PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase. Nature 1994;370:71–75.

    Article  PubMed  CAS  Google Scholar 

  20. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990;61:203–212.

    Article  PubMed  CAS  Google Scholar 

  21. Ueki K, Algenstaedt P, Mauvais-Jarvis F, Kahn CR. Positive and negative regulation of phosphoinositide 3-kinase-dependent signaling pathways by three different gene products of the p85a regulatory subunit. Mol Cell Biol 2000;20:8035–8046.

    Article  PubMed  CAS  Google Scholar 

  22. Whitman M, Downes CP, Keeler M, Keller T, Cantley L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature 1988;332:644–646.

    Article  PubMed  CAS  Google Scholar 

  23. Chan T, Rittenhouse S, Tsichlis P. AKT/PKB and other D3 phosphoinostide regulated kinases: kinase acitivation by phosphoimositide-dependent phosporylation. Annu Rev Biochem 1998;68:965–1014.

    Article  Google Scholar 

  24. Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S. Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci USA 1998;95:11211–11216.

    Article  PubMed  CAS  Google Scholar 

  25. Persad S, et al. Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343. J Biol Chem 2001;276:27462–27469.

    Article  PubMed  CAS  Google Scholar 

  26. Feng J, Park J, Cron P, Hess D, Hemmings BA. Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J Biol Chem 2004;279:41189–41196.

    Article  PubMed  CAS  Google Scholar 

  27. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098–1101.

    Article  PubMed  CAS  Google Scholar 

  28. Jacinto E, Hall MN. Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 2003;4:117–126.

    Article  PubMed  CAS  Google Scholar 

  29. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002;4:648–657.

    Article  PubMed  CAS  Google Scholar 

  30. Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 2002;4:658–665.

    Article  PubMed  CAS  Google Scholar 

  31. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phoshpoinositide-3-kinase/akt pathway. Mol Cell 2002;10:151–162.

    Article  PubMed  CAS  Google Scholar 

  32. Liu MY, Cai S, Espejo A, Bedford MT, Walker CL. 14–3-3 interacts with the tumor suppressor tuberin at Akt phosphorylation site(s). Cancer Res 2002;62:6475–6480.

    PubMed  CAS  Google Scholar 

  33. Li Y, Inoki K, Yeung R, Guan KL. Regulation of TSC2 by 14–3-3 binding. J Biol Chem 2002;277:44593–44596.

    Article  PubMed  CAS  Google Scholar 

  34. del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G. Interleukin-3 phosphorylation of BAD through the protein kinase Akt. Science 1997;278:687–689.

    Article  PubMed  Google Scholar 

  35. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997;91:231–241.

    Article  PubMed  CAS  Google Scholar 

  36. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi P. Phosphorylation and functional inactivation of TSC2 by Erk: implications for tuberous sclerosis and cancer pathogenesis. Cell 2005;121:179–193.

    Article  PubMed  CAS  Google Scholar 

  37. Tee AR, et al. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci USA 2002 99:13571–13576.

    Article  PubMed  CAS  Google Scholar 

  38. Zhang Y, et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 2003;5:578–581.

    Article  PubMed  CAS  Google Scholar 

  39. Saucedo LJ, et al. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 2003;5:566–571.

    Article  PubMed  CAS  Google Scholar 

  40. Stocker H, et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 2003;5:559–565.

    Article  PubMed  CAS  Google Scholar 

  41. Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 2003;15:1829–1834.

    Article  CAS  Google Scholar 

  42. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol 2005;15:702–713.

    Article  PubMed  CAS  Google Scholar 

  43. Holz MK, Blenis J. Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J Biol Chem 2005;280:26089–26093.

    Article  PubMed  CAS  Google Scholar 

  44. Kim DH, et al. G#x003B2;L, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003;4:895–904.

    Article  Google Scholar 

  45. Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, Oppliger W, Jenoe P, Hall MN. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 2002; 10:457–468.

    Article  PubMed  CAS  Google Scholar 

  46. Brunn SJ, Hudson CC, Sekulic A, Williams JM, Hosoi H, Houghton PJ, Lawrence JC Jr, Abraham RT. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 1997; 277:99–101.

    Article  PubMed  CAS  Google Scholar 

  47. Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA 1998;95:1432–1437.

    Article  PubMed  CAS  Google Scholar 

  48. Schalm SS, Blenis J. Identification of a conserved motif required for mTOR signaling. Curr Biol 2002;12:632–639.

    Article  PubMed  CAS  Google Scholar 

  49. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002;110:177–189.

    Google Scholar 

  50. Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002;110:163–175.

    Article  PubMed  CAS  Google Scholar 

  51. Schalm SS, Fingar DC, Sabatini DM, Blenis J. TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol 2003;13:797–806.

    Article  PubMed  CAS  Google Scholar 

  52. Nojima H, et al. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem 2003;278:15461–15464.

    Article  PubMed  CAS  Google Scholar 

  53. Mader S, Lee H, Pause A, Sonenberg N. The translation initiation factor eIF-4E binds to a common motif shared by the translation factor eIF-4G and the translational repressor 4E-binding proteins. Mol Cell Biol 1995;15:4990–4997.

    PubMed  CAS  Google Scholar 

  54. Pause A, Belsham GJ, Gingras AC, Donze O, Lin TA, Lawrence JC, Sonenberg N. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5’cap function. Nature 1994;371:762–767.

    Article  PubMed  CAS  Google Scholar 

  55. Rosenwald IB, Kaspar R, Rousseau D, Gehrke L, Leboulch P, Chen JJ, Schmidt EV, Sonenberg N, London IM. Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. J Biol Chem 1995;270:21176–21180.

    Article  PubMed  CAS  Google Scholar 

  56. Hashemolhosseini S, Nagamine Y, Morley SJ, Desrivieres S, Mercep L, Ferrari S. Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J Biol Chem 1998; 273:14424–14429.

    Article  PubMed  CAS  Google Scholar 

  57. Shantz LM, Pegg AE. Overproduction of ornithine decarboxylase caused by relief of translational repression is associated with neoplastic transformation. Cancer Res 1994;54:2313–2316.

    PubMed  CAS  Google Scholar 

  58. DeBenedetti A, Joshi B, Graff JR, Zimmer SG. CHO cells transformed by the translation factor eIF4E display increased c-myc expression but require overexpression of Max for tumorigenicity. Mol Cell Differ 1994;2:347–371.

    CAS  Google Scholar 

  59. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, Semenza GL. Modulation of hypoxia-inducible factor 1 alpha expression by the epidermal growth factor/phosphatidylinositol3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000;60:1541–1545.

    PubMed  CAS  Google Scholar 

  60. Mayerhofer M, Valent P, Sperr WR, Griffin JD, Sillaber C. BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood 2002;100:3767–3775.

    Article  PubMed  CAS  Google Scholar 

  61. Wang X, et al. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J 2001;20:4370–4379.

    Article  PubMed  CAS  Google Scholar 

  62. Harrington LS, et al The TSC1–2 tumor suppressor controls insulin-P13K signaling via regulation of IRS proteins. J Cell Biol 2004;166:213–223.

    Article  PubMed  CAS  Google Scholar 

  63. Thomas G, Sabatini DM Hall MN (editors). Tor (Target of Rapamycin). In: Current Topics in Microbiology and Immunology, Vol 279 (2004). Nutrient Signaling Through TOR Kinases Controls Gene Expression and Cellular Differentiation in Fungi J.R. Rohde, M.E. Cardenas p. 53–72.

    Google Scholar 

  64. Huang S, Bjornsti MA, Houghton PJ. Rapamycins: Mechanisms of action and cellular resistance. Cancer Biol Ther 2003;2:222–232.

    PubMed  CAS  Google Scholar 

  65. Stocker H, et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 2003;5:559–565.

    Article  PubMed  CAS  Google Scholar 

  66. Long X, Ortiz-Vega S, Lin Y, Avruch J. Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. J Biol Chem 2005;280:23433–23436.

    Article  PubMed  CAS  Google Scholar 

  67. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 2003;13:1259–1268.

    Article  PubMed  CAS  Google Scholar 

  68. Gao X, et al. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 2002;4:699–704.

    Article  PubMed  CAS  Google Scholar 

  69. Smith EM, Finn SG, Tee AR, Browne GJ, Proud CG. The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses. J Biol Chem 2005;280:18717–18727.

    Article  PubMed  CAS  Google Scholar 

  70. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115:577–590.

    Article  PubMed  CAS  Google Scholar 

  71. Woods A, et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 2003;13:2004–2008.

    Article  PubMed  CAS  Google Scholar 

  72. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA 2004 Mar 9;101(10):3329–3335.

    Google Scholar 

  73. Arsham AM, Howell JJ, Simon MC. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J Biol Chem 2003:278:29655–29660.

    Article  PubMed  CAS  Google Scholar 

  74. Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 2004;24:200–216.

    Article  PubMed  CAS  Google Scholar 

  75. Dilling, MB, et al. 4E-binding proteins, the suppressors of eukaryotic initiation factor 4E, are down-regulated in cells with acquired or intrinsic resistance to rapamycin. J Biol Chem 2002;277:13907–13917.

    Article  PubMed  CAS  Google Scholar 

  76. Nourse J, et al. Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. Nature 1994;372: 570–573.

    Article  PubMed  CAS  Google Scholar 

  77. Barata JT, Cardoso AA, Nadler LM, and Boussiotis VA. Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27(kip1). Blood 2001;98:1524–1531.

    Article  PubMed  CAS  Google Scholar 

  78. Law BK, et al. Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells. Mol Cell Biol 2002;22:8184–8198.

    Article  PubMed  CAS  Google Scholar 

  79. Jiang H, Coleman J, Miskimins R, Miskimins WK. Expression of constitutively active 4EBP-1 enhances p27Kip1 expression and inhibits proliferation of MCF7 breast cancer cells. Cancer Cell Int 2003; 3:2.

    Google Scholar 

  80. Lieberthal W, et al. Rapamycin impairs recovery from acute renal failure: role of cell-cycle arrest and apoptosis of tubular cells. Am J Physiol Renal Physiol 2001;281:693–706.

    Google Scholar 

  81. Woltman AM, et al. Rapamycin specifically interferes with GM-CSF signaling in human dendritic cells, leading to apoptosis via increased p27KIP1 expression. Blood 2003;101:1439–1445.

    Article  PubMed  CAS  Google Scholar 

  82. Secombe J, Pierce SB, Eisenman RN. Myc: a weapon of mass destruction. Cell 2004;117:153–156.

    Article  PubMed  CAS  Google Scholar 

  83. Datta SR, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997;91:231–241.

    Article  PubMed  CAS  Google Scholar 

  84. Zha J, Harada H, Yang E, Jockel J, Korsmeyer Sj. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14–3-3 not BCL-X(L). Cell 1996;87:619–628.

    Article  PubMed  CAS  Google Scholar 

  85. Wendel HG, et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 2004;428:332–337.

    Article  PubMed  CAS  Google Scholar 

  86. Huang S, Liu LN, Hosoi H, Dilling MB, Shikata T, Houghton PJ. p53/p21(CIP1) cooperate in enforcing rapamycin-induced G(1) arrest and determine the cellular response to rapamycin. Cancer Res 2001;61:3373–3381.

    PubMed  CAS  Google Scholar 

  87. Huang S, et al. Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1). Mol Cell 2003;11:1491–1501.

    Article  PubMed  CAS  Google Scholar 

  88. Podsypanina K, et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice. Proc Natl Acad Sci USA 2001;98:10320–10325.

    Article  PubMed  CAS  Google Scholar 

  89. Neshat MS, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 2001;98:10314–10319.

    Article  PubMed  CAS  Google Scholar 

  90. Shi Y, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 2002;62:5027–5034.

    PubMed  CAS  Google Scholar 

  91. Guba M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002;8:128–135.

    Article  PubMed  CAS  Google Scholar 

  92. Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL, Van Obberghen E. Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J Biol Chem 2002;277:27975–27981.

    Article  PubMed  CAS  Google Scholar 

  93. Zhong H, et al. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000;60:1541–1545.

    PubMed  CAS  Google Scholar 

  94. Zundel W, et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev 2000;14:391–396.

    PubMed  CAS  Google Scholar 

  95. Jiang BH, et al. Phosphatidylinositol 3-kinase signaling controls levels of hypoxia-inducible factor 1. Cell Growth Differ 2001;12:363–369.

    PubMed  CAS  Google Scholar 

  96. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 2001;21:3995–4004.

    Article  PubMed  CAS  Google Scholar 

  97. Mayerhofer M, Valent P, Sperr WR, Griffin JD, Sillaber C. BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood 2002;100:3767–3775.

    Article  PubMed  CAS  Google Scholar 

  98. Li J, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human, brain, breast, and prostate cancer. Science 1997;275:1943–1947.

    Article  PubMed  CAS  Google Scholar 

  99. Steck PA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997;15:356–362.

    Article  PubMed  CAS  Google Scholar 

  100. Risinger JI, Hayes AK, Berchuck A, Barrett JC. PTEN/MMAC1 mutations in endometrial cancers. Cancer Res 1997;57:4736–4738.

    Google Scholar 

  101. Park WS, Moon YW, Yang YM, Kim YS, Kim YD, Fuller BG, Vortmeyer AO, Fogt F, Lubensky IA, Zhuang Z. Mutations of the STK11 gene in sporadic gastric carcinoma. Int J Oncol 1998;3:601–604.

    Google Scholar 

  102. Wong AS, Kim SO, Leung PC, Auersperg N, Pelech SL. Profiling of protein kinases in the neoplastic transformation of human ovarian surface epithelium. Gynecol Oncol 2001;82:305–311.

    Article  PubMed  CAS  Google Scholar 

  103. Couch FJ, Wang XY, Wu GJ, Qian J, Jenkins RB, James CD. Localization of PS6K to chromosomal region 17q23 and determination of its amplification in breast cancer. Cancer Res 1999;59:1408–1411.

    PubMed  CAS  Google Scholar 

  104. Haydon MS, Googe JD, Sorrells DS, Ghali GE, Li BD. Progression of eIF4e gene amplification and overexpression in benign and malignant tumors of the head and neck. Cancer 2000;88:2803–2810.

    Article  PubMed  CAS  Google Scholar 

  105. Sorrells DL, Meschonat C, Black D, Li BD. Pattern of amplification and overexpression of the eukaryotic initiation factor 4E gene in solid tumor. J Surg Res 1999;85;37–42.

    Article  PubMed  CAS  Google Scholar 

  106. Wang S, et al. Expression of eukaryotic translation initiation factors 4E and 2alpha correlates with the progression of thyroid carcinoma. Thyroid 2001;1:1101–1107.

    Article  Google Scholar 

  107. Berkel HJ, Turbat-Herrera EA, Shi R, de Benedetti A. Expression of the translation initiation factor eIF4E in the polyp-cancer sequence in the colon. Cancer Epidemiol Biomarkers Prev 2001;10:663–666.

    Google Scholar 

  108. Rosenwald IB, et al. Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. Oncogene 1999;18: 2507–2517.

    Article  PubMed  CAS  Google Scholar 

  109. Li BD, et al. Prospective study of eukaryotic initiation factor 4E protein elevation and breast cancer outcome. Ann Surg 2002;235:732–738.

    Article  PubMed  Google Scholar 

  110. Crew JP, et al. Eukaryotic initiation factor-4E in superficial and muscle invasive bladder cancer and its correlation with vascular endothelial growth factor expression and tumour progression. Br J Cancer 2000;82: 161–166.

    Article  PubMed  CAS  Google Scholar 

  111. Scott PA, et al. Differential expression of vascular endothelial growth factor mRNA vs protein isoform expression in human breast cancer and relationship to eIF-4E. Br J Cancer 1998;77:2120–2128.

    PubMed  CAS  Google Scholar 

  112. Ruggero D, et al. The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 2004;10:484–486.

    Article  PubMed  CAS  Google Scholar 

  113. Martin ME, et al. 4E binding protein 1 expression is inversely correlated to the progression of gastrointestinal cancers. Int J Biochem Cell Biol 2000;32:633–642.

    Article  PubMed  CAS  Google Scholar 

  114. Choi J, Chen J, Schreiber SL, Clardy, J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 1996;273:239–242.

    Article  PubMed  CAS  Google Scholar 

  115. Metcalf CEA, et al. Structure-based dosing of AP23573, a phosphorous-containing analog of rapamycin for anti-tumor therapy. Proc Am Assoc Cancer Res. Orlando, Florida. 2004;ab: 2476.

    Google Scholar 

  116. Douros J, Suffness M. New antitumor substances of natural origin. Cancer Treat Rev 1981;8:63–87.

    Article  PubMed  CAS  Google Scholar 

  117. Houchens DP, Ovejera AA, Riblet SM, Slagel DE. Human brain tumor xenografts in nude mice as a chemotherapy model. Eur J Cancer Clin Oncol 1983;19:799–805.

    Article  PubMed  CAS  Google Scholar 

  118. Eng CP, Sehgal SN, Vezina C. Activity of rapamycin (AY-22,989) against transplanted tumors. J Antibiot (Tokyo) 1984;37:1231–1237.

    CAS  Google Scholar 

  119. Dilling MB, Dias P, Shapiro DN, Germain GS, Johnson RK, Houghton PJ. Rapamycin selectively inhibits the growth of childhood rhabdomyosarcoma cells through inhibition of signaling via the type I insulin-like growth factor receptor. Cancer Res 1994;54:903–907.

    PubMed  CAS  Google Scholar 

  120. Shi Y, Frankel A, Radvanyi LG, Penn LZ, Miller RG, Mills GB. Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro. Cancer Res 1995;55:1982–1988.

    PubMed  CAS  Google Scholar 

  121. Seufferlein T, Rozengurt E. Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells. Cancer Res 1996;56:3895–3897.

    PubMed  CAS  Google Scholar 

  122. Hosoi H, Dilling MB, Liu LN, Danks MK, Shikata T, Sekulic A, Abraham RT, Lawrence JC Jr, Houghton PJ. Studies on the mechanism of resistance to rapamycin in human cancer cells. Mol Pharmacol 1998;54:815–824.

    PubMed  CAS  Google Scholar 

  123. Hosoi H, Dilling MB, Shikata T, Liu LN, Shu L, Ashmun RA, Germain GS, Abraham RT, Houghton PJ. Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells. Cancer Res 1999;59:886–894.

    PubMed  CAS  Google Scholar 

  124. Geoerger B, Kerr K, Tang CB, Fung KM, Powell B, Sutton LN, Phillips PC, Janss AJ. Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res 2001;61:1527–1532.

    PubMed  CAS  Google Scholar 

  125. Ogawa T, Tokuda M, Tomizawa K, Matsui H, Itano T, Konishi R, Nagahata S, Hatase O. Osteoblastic differentiation is enhanced by rapamycin in rat osteoblast-like osteosarcoma (ROS 17/2.8) cells. Biochem Biophys Res Commun 1998;249:226–230.

    Article  PubMed  CAS  Google Scholar 

  126. Grewe M, Gansauge F, Schmid RM, Adler G, Seufferlein T. Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-S6K1 pathway in human pancreatic cancer cells. Cancer Res 1999; 59:3581–3587.

    PubMed  CAS  Google Scholar 

  127. Shah SA, Potter MW, Ricciardi R, Perugini RA, Callery MP. Frap-S6K1 signaling is required for pancreatic cancer cell proliferation. J Surg Res 2001;97:123–130.

    Article  PubMed  CAS  Google Scholar 

  128. Gibbons JJ, Discafani C, Peterson R, Hernandez R, Skotnicki J, Frost P. The effect of CCI-779, a novel macrolide anti-tumor agent, on the growth of human tumor cells in vitro and in nude mouse xenografts in vivo. Proc Am Assoc Cancer Res 1999;40:301.

    Google Scholar 

  129. Yu K, Zhang W, Lucas J, Toral-Barza L, Peterson R, Skotnicki J, Frost P, Gibbons J. Deregulated PI3K/AKT/TOR pathway in PTEN-deficient tumor cells correlates with an increased growth inhibition sensitivity to a TOR kinase inhibitor CCI-779. Proc Am Assoc Cancer Res 2001;42:802.

    Google Scholar 

  130. Yu K, Toral-Barza L, Discafani C, Zhang WG, Skotnicki J, Frost P, Gibbons JJ. MTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 2001;8:249–258.

    Article  PubMed  Google Scholar 

  131. Hultsch T, Martin R, Hohman RJ. The effect of the immunophilin ligands rapamycin and FK506 on proliferation of mast cells and other hematopoietic cell lines. Mol Biol Cell 1992;3:981–987.

    PubMed  CAS  Google Scholar 

  132. Gottschalk AR, Boise LH, Thompson CB, Quintans J. Identification of immunosuppressant-induced apoptosis in a murine B-cell line and its prevention by bcl-x but not bcl-2. Proc Natl Acad Sci USA 1994;91:7350–7354.

    Article  PubMed  CAS  Google Scholar 

  133. Muthukkumar S, Ramesh TM, Bondada S. Rapamycin, A potent immunosuppressive drug, causes programmed cell death in B lymphoma cells. Transplantation 1995;60:264–270.

    Article  PubMed  CAS  Google Scholar 

  134. Mateo-Lozano S, Tirado OM, Notario V. Rapamycin induces the fusion-type independent downregulation of the EWS/FLI-1 proteins and inhibits Ewing’s sarcoma cell proliferation. Oncogene 2003;22:9282–9287.

    Article  PubMed  CAS  Google Scholar 

  135. Dancey JE. Clinical development of mammalian target of rapamycin inhibitors. Hematol Oncol Clin North Am 2002;16:1101–1114.

    Article  PubMed  Google Scholar 

  136. Atkins MB, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004;22:909–918.

    Article  PubMed  CAS  Google Scholar 

  137. Witzig TE, et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005;23:5347–5356.

    Article  PubMed  CAS  Google Scholar 

  138. Chan S, et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 2005;23:5314–5322

    Article  PubMed  CAS  Google Scholar 

  139. O’Donnell A, et al. A phase I study of the oral mTOR inhibitor RAD001 as monotherapy to identify the optimal biologically effective dose using toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints in patients with solid tumours. Proc Am Soc Clin Oncol 2003;22:200.

    Google Scholar 

  140. Boulay A, et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 2004;64:252–261.

    Article  PubMed  CAS  Google Scholar 

  141. Raje N, et al. Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood 2004;104:4188–4193.

    Article  PubMed  CAS  Google Scholar 

  142. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001;293:876–880.

    Article  PubMed  CAS  Google Scholar 

  143. Mohi MG, et al. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci USA 2004;101:3130–3135.

    Article  PubMed  CAS  Google Scholar 

  144. Gemmill RM, Zhou M, Costa L, Korch C, Bukowski RM, Drabkin HA. Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma. Br J Cancer 2005;92:2266–2277.

    Article  PubMed  CAS  Google Scholar 

  145. Edwards E, Geng L, Tan J, Onishko H, Donnelly E, Hallahan DE. Phosphatidylinositol 3-kinase/Akt signaling in the response of vascular endothelium to ionizing radiation. Cancer Res 2002;62:4671–4677.

    PubMed  CAS  Google Scholar 

  146. Tan J, Hallahan DE. Growth factor-independent activation of protein kinase B contributes to the inherent resistance of vascular endothelium to radiation-induced apoptotic response. Cancer Res 2003;63:7663–7667.

    PubMed  CAS  Google Scholar 

  147. Shinohara ET, Cao C, Niermann K, Mu Y, Zeng F, Hallahan DE, Lu B. Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene 2005;24:1–9.

    Article  CAS  Google Scholar 

  148. Sawyers CL. Finding the next Gleevec: FLT3 targeted kinase inhibitor therapy for acute myeloid leukemia. Cancer Cell 2002;5:413–415.

    Article  Google Scholar 

  149. Hentges KE, et al. FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse. Proc Natl Acad Sci USA 2001;98:13796–13801.

    Google Scholar 

  150. Hentges K, Thompson K, Peterson A. The flat-top gene is required for the expansion and regionalization of the telencephalic primordium. Development 1999;126:1601–1609.

    PubMed  CAS  Google Scholar 

Download references

Authors
  1. John B. Easton PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter J. Houghton PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Surgical Oncology, Columbia University, New York, NY

    Howard L. Kaufman

  2. Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College Cornell University, New York, NY

    Scott Wadler

  3. Boston University Medical Campus Boston University School of Medicine, Boston, MA

    Karen Antman

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press

About this chapter

Cite this chapter

Easton, J.B., Houghton, P.J. (2008). mTOR. In: Kaufman, H.L., Wadler, S., Antman, K. (eds) Molecular Targeting in Oncology. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-337-0_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-337-0_2

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-577-4

  • Online ISBN: 978-1-59745-337-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation