Targeting mTOR Signaling Pathways in Liver Disease

  • Hala E. Thomas
  • Sara C. KozmaEmail author


Over the last 15 years, the Ser/Thr protein kinase mammalian target of rapamycin (mTOR) has emerged as a critical regulator of cell growth, proliferation, apoptosis, and metabolism [1]. The diversity of intracellular responses, in which mTOR is implicated, stems from the fact that it integrates input from distinct signaling effectors (growth factors and nutrients) and acts on specific substrates depending on its ­interaction in multienzyme protein complexes termed mTOR complexes [1]. In addition, mTOR signaling is negatively regulated by several tumor suppressors. In a largely selective manner, the macrolide antibiotic rapamycin inhibits the activity of one of the mTOR complexes, mTOR Complex1 (mTORC1, see below). Rapamycin (sirolimus) and its derivatives (AP23573, CCI-779, and RAD001) are used in the clinic as immunosuppressive agents in organ transplantation and as antiproliferative and antiangiogenic agents to prevent coronary restenosis and treat cancer. Here, we will review the molecular mechanisms known to regulate mTOR signaling pathways, illustrate the role of mTOR signaling in liver disease, and report on the preclinical and clinical studies targeting mTOR to treat liver cancer.


  1. 1.
    Dann SG, Selvaraj A, Thomas G (2007) mTOR complex1–S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med 13(6):252–259PubMedCrossRefGoogle Scholar
  2. 2.
    Kim DH, Sarbassov DD, Ali SM et al (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110(2):163–175PubMedCrossRefGoogle Scholar
  3. 3.
    Kim DH, Sarbassov dos D, Ali SM et al (2003) GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 11(4):895–904PubMedCrossRefGoogle Scholar
  4. 4.
    Hara K, Maruki Y, Long X et al (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110(2):177–189PubMedCrossRefGoogle Scholar
  5. 5.
    Loewith R, Jacinto E, Wullschleger S et al (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10(3): 457–468PubMedCrossRefGoogle Scholar
  6. 6.
    Haar EV, Lee SI, Bandhakavi S et al (2007) Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 9:316–323CrossRefGoogle Scholar
  7. 7.
    Schalm SS, Blenis J (2002) Identification of a conserved motif required for mTOR signaling. Curr Biol 12(8): 632–639PubMedCrossRefGoogle Scholar
  8. 8.
    Jacinto E, Lorberg A (2008) TOR regulation of AGC kinases in yeast and mammals. Biochem J 410(1):19–37PubMedCrossRefGoogle Scholar
  9. 9.
    Banko JL, Hou L, Poulin F et al (2006) Regulation of eukaryotic initiation factor 4E by converging signaling pathways during metabotropic glutamate receptor-dependent long-term depression. J Neurosci 26(8):2167–2173PubMedCrossRefGoogle Scholar
  10. 10.
    Sarbassov DD, Ali SM, Kim DH et al (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14(14):1296–1302PubMedCrossRefGoogle Scholar
  11. 11.
    Jacinto E, Loewith R, Schmidt A et al (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6(11):1122–1128PubMedCrossRefGoogle Scholar
  12. 12.
    Yang Q, Inoki K, Ikenoue T et al (2006) Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev 20(20): 2820–2832PubMedCrossRefGoogle Scholar
  13. 13.
    Frias MA, Thoreen CC, Jaffe JD et al (2006) mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 16(18):1865–1870PubMedCrossRefGoogle Scholar
  14. 14.
    Sarbassov DD, Guertin DA, Ali SM et al (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101PubMedCrossRefGoogle Scholar
  15. 15.
    Pearce LR, Huang X, Boudeau J et al (2007) Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J 405(3):513–522PubMedCrossRefGoogle Scholar
  16. 16.
    Thedieck K, Polak P, Kim ML et al (2007) PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS ONE 2(11):e1217CrossRefGoogle Scholar
  17. 17.
    Woo SY, Kim DH, Jun CB et al (2007) PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J Biol Chem 282(35):25604–25612PubMedCrossRefGoogle Scholar
  18. 18.
    Lee YH, White MF (2004) Insulin receptor substrate proteins and diabetes. Arch Pharm Res 27(4):361–370PubMedCrossRefGoogle Scholar
  19. 19.
    Taniguchi CM, Ueki K, Kahn R (2005) Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. J Clin Invest 115(3):718–727PubMedGoogle Scholar
  20. 20.
    Zick Y (2001) Insulin resistance: a phosphorylation-based uncoupling of insulin signaling. Trends Cell Biol 11(11): 437–441PubMedCrossRefGoogle Scholar
  21. 21.
    Pawson T (1995) Protein modules and signalling networks. Nature 373:573–579PubMedCrossRefGoogle Scholar
  22. 22.
    Fruman DA, Meyers RE, Cantley LC (1998) Phosphoinositide kinases. Annu Rev Biochem 67:481–507PubMedCrossRefGoogle Scholar
  23. 23.
    Maehama T, Dixon JE (1999) PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol 9(4):125–128PubMedCrossRefGoogle Scholar
  24. 24.
    Roux PP, Ballif BA, Anjum R et al (2004) Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci U S A 101(37):13489–13494PubMedCrossRefGoogle Scholar
  25. 25.
    Ma L, Chen Z, Erdjument-Bromage H et al (2005) Phos­phorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121(2):179–193PubMedCrossRefGoogle Scholar
  26. 26.
    Rodriguez-Viciana P, Warne PH, Dhand R et al (1994) Phos­phatidylinositol-3-OH kinase as a direct target of Ras. Nature 370(6490):527–532PubMedCrossRefGoogle Scholar
  27. 27.
    Garami A, Zwartkruis FJ, Nobukuni T et al (2003) Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 11(6):1457–1466PubMedCrossRefGoogle Scholar
  28. 28.
    Long X, Lin Y, Ortiz-Vega S et al (2005) Rheb Binds and Regulates the mTOR Kinase. Curr Biol 15(8):702–713PubMedCrossRefGoogle Scholar
  29. 29.
    Byfield MP, Murray JT, Backer JM (2005) hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J Biol Chem 280(38):33076–33082PubMedCrossRefGoogle Scholar
  30. 30.
    Nobukuni T, Joaquin M, Roccio M et al (2005) Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci U S A 102(40):14238–14243PubMedCrossRefGoogle Scholar
  31. 31.
    Zhang Y, Guo K, LeBlanc RE et al (2007) Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes 56(6):1647–1654PubMedCrossRefGoogle Scholar
  32. 32.
    Nobukuni T, Kozma SC, Thomas G (2007) hvps34, an ancient player, enters a growing game: mTOR Complex1/S6K1 signaling. Curr Opin Cell Biol 19(2):135–141PubMedCrossRefGoogle Scholar
  33. 33.
    Gulati P, Gaspers LD, Dann SG et al (2008) Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell Metab 7(5):456–465PubMedCrossRefGoogle Scholar
  34. 34.
    Sancak Y, Peterson TR, Shaul YD et al (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320(5882):1496–1501PubMedCrossRefGoogle Scholar
  35. 35.
    Kim E, Goraksha-Hicks P, Li L et al (2008) Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10:935–945PubMedCrossRefGoogle Scholar
  36. 36.
    Dennis PB, Jaeschke A, Saitoh M et al (2001) Mammalian TOR: a homeostatic ATP sensor. Science 294(5544): 1102–1105PubMedCrossRefGoogle Scholar
  37. 37.
    Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115(5):577–590PubMedCrossRefGoogle Scholar
  38. 38.
    Shaw RJ, Bardeesy N, Manning BD et al (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6(1):91–99PubMedCrossRefGoogle Scholar
  39. 39.
    Fang Y, Vilella-Bach M, Bachmann R et al (2001) Phos­phatidic acid-mediated mitogenic activation of mTOR signaling. Science 294(5548):1942–1945PubMedCrossRefGoogle Scholar
  40. 40.
    Volarevic S, Stewart MJ, Ledermann B et al (2000) Prolif­eration, but not growth, blocked by conditional deletion of 40S ribosomal protein S6. Science 288(5473):2045–2047PubMedCrossRefGoogle Scholar
  41. 41.
    Fumagalli S, Thomas G (2000) S6 phosphorylation and signal transduction. In: Sonenberg N, Hershey JWB, Mathews M (eds) Translational control of gene expression. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, pp 695–717Google Scholar
  42. 42.
    Roux PP, Shahbazian D, Vu H et al (2007) RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem 282(19):14056–14064PubMedCrossRefGoogle Scholar
  43. 43.
    Holland EC, Sonenberg N, Pandolfi PP et al (2004) Signaling control of mRNA translation in cancer pathogenesis. Onco­gene 23(18):3138–3144PubMedCrossRefGoogle Scholar
  44. 44.
    Raught B, Peiretti F, Gingras AC et al (2004) Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. Embo J 23(8):1761–1769PubMedCrossRefGoogle Scholar
  45. 45.
    Wang X, Li W, Williams M et al (2001) Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. Embo J 20(16):4370–4379PubMedCrossRefGoogle Scholar
  46. 46.
    Harada H, Andersen JS, Mann M et al (2001) p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci U S A 98(17): 9666–9670PubMedCrossRefGoogle Scholar
  47. 47.
    Richardson CJ, Broenstrup M, Fingar DC et al (2004) SKAR is a specific target of S6 kinase 1 in cell growth control. Curr Biol 14(17):1540–1549PubMedCrossRefGoogle Scholar
  48. 48.
    Dorrello NV, Peschiaroli A, Guardavaccaro D et al (2006) S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 314(5798): 467–471PubMedCrossRefGoogle Scholar
  49. 49.
    Gingras AC, Raught B, Sonenberg N (2001) Regulation of translation initiation by FRAP/mTOR. Genes Dev 15(7):807–826PubMedCrossRefGoogle Scholar
  50. 50.
    Lynch CJ, Hutson SM, Patson BJ et al (2002) Tissue-specific effects of chronic dietary leucine and norleucine supplementation on protein synthesis in rats. Am J Physiol Endocrinol Metab 283(4):E824–E835Google Scholar
  51. 51.
    Carvalho L, Parise ER (2006) Evaluation of nutritional status of nonhospitalized patients with liver cirrhosis. Arq Gastroenterol 43(4):269–274PubMedCrossRefGoogle Scholar
  52. 52.
    Khanna S, Gopalan S (2007) Role of branched-chain amino acids in liver disease: the evidence for and against. Curr Opin Clin Nutr Metab Care 10(3):297–303PubMedCrossRefGoogle Scholar
  53. 53.
    Alberino F, Gatta A, Amodio P et al (2001) Nutrition and survival in patients with liver cirrhosis. Nutrition 17(6):445–450PubMedCrossRefGoogle Scholar
  54. 54.
    Marchesini G, Bianchi G, Merli M et al (2003) Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastro­enterology 124(7):1792–1801PubMedCrossRefGoogle Scholar
  55. 55.
    Henkel AS, Buchman AL (2006) Nutritional support in patients with chronic liver disease. Nat Clin Pract Gastro­enterol Hepatol 3(4):202–209PubMedCrossRefGoogle Scholar
  56. 56.
    Um SH, Frigerio F, Watanabe M et al (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431(7005):200–205PubMedCrossRefGoogle Scholar
  57. 57.
    Harrington LS, Findlay GM, Gray A et al (2004) The TSC1–2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 166(2):213–223PubMedCrossRefGoogle Scholar
  58. 58.
    Shah OJ, Wang Z, Hunter T (2004) Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 14(18):1650–1656PubMedCrossRefGoogle Scholar
  59. 59.
    Jaeschke A, Hartkamp J, Saitoh M et al (2002) Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent. J Cell Biol 159(2):217–224PubMedCrossRefGoogle Scholar
  60. 60.
    Hara K, Yonezawa K, Weng QP et al (1998) Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem 273(23):14484–14494PubMedCrossRefGoogle Scholar
  61. 61.
    Patti ME, Brambilla E, Luzi L et al (1998) Bidirectional modulation of insulin action by amino acids. J Clin Invest 101(7):1519–1529PubMedCrossRefGoogle Scholar
  62. 62.
    Tremblay F, Marette A (2001) Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells. J Biol Chem 276(41):38052–38060PubMedGoogle Scholar
  63. 63.
    Felig P, Marliss E, Cahill GF Jr (1969) Plasma amino acid levels and insulin secretion in obesity. N Engl J Med 281(15): 811–816PubMedCrossRefGoogle Scholar
  64. 64.
    Felig P, Marliss E, Cahill GF Jr (1970) Are plasma amino acid levels elevated in obesity? N Engl J Med 282(3):166PubMedGoogle Scholar
  65. 65.
    Felig P, Wahren J, Hendler R et al (1974) Splanchnic glucose and amino acid metabolism in obesity. J Clin Invest 53(2): 582–590PubMedCrossRefGoogle Scholar
  66. 66.
    Krebs M, Brehm A, Krssak M et al (2003) Direct and indirect effects of amino acids on hepatic glucose metabolism in humans. Diabetologia 46(7):917–925PubMedCrossRefGoogle Scholar
  67. 67.
    Krebs M, Krssak M, Bernroider E et al (2002) Mechanism of amino acid-induced skeletal muscle insulin resistance in humans. Diabetes 51(3):599–605PubMedCrossRefGoogle Scholar
  68. 68.
    Ueno M, Carvalheira JB, Tambascia RC et al (2005) Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway. Diabetologia 48(3):506–518PubMedCrossRefGoogle Scholar
  69. 69.
    Tremblay F, Brule S, Hee Um S et al (2007) Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance. Proc Natl Acad Sci U S A 104(35):14056–14061PubMedCrossRefGoogle Scholar
  70. 70.
    Um SH, D’Alessio D, Thomas G (2006) Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab 3(6):393–402PubMedCrossRefGoogle Scholar
  71. 71.
    Aloni R, Peleg D, Meyuhas O (1992) Selective translational control and nonspecific posttransciptional regulation of ribosomal protein gene expression during development and regeneration of rat liver. Mol Cell Biol 12:2203–2212PubMedGoogle Scholar
  72. 72.
    Nabeshima YI, Ogata K (1980) Stimulation of the synthesis of ribosomal proteins in regenerating rat liver with special reference to the increase in the amounts of effective mRNAs for ribosomal proteins. Eur J Biochem 107(2):323–329PubMedCrossRefGoogle Scholar
  73. 73.
    Perry RP (2005) The architecture of mammalian ribosomal protein promoters. BMC Evol Biol 5(1):15PubMedCrossRefGoogle Scholar
  74. 74.
    Levy S, Avni D, Hariharan N et al (1991) Oligopyrimidine tract at the 5’ end of mammalian ribosomal protein mRNAs is required for their translational control. Proc Natl Acad Sci USA 88:3319–3323PubMedCrossRefGoogle Scholar
  75. 75.
    Jefferies HBJ, Fumagalli S, Dennis PB et al (1997) Rapamycin suppresses 5’TOP mRNA translation through inhibition of p70s6k. EMBO J 12:3693–3704CrossRefGoogle Scholar
  76. 76.
    Terada N, Patel HR, Takase K et al (1994) Rapamycin selectively inhibits translation of mRNAs encoding elongation factors and ribosomal proteins. Proc Natl Acad Sci U S A 91:11477–11481PubMedCrossRefGoogle Scholar
  77. 77.
    Jefferies HBJ, Reinhard C, Kozma SC et al (1994) Rapamycin selectively represses translation of the “polypyrimidine tract” mRNA family. Proc Natl Acad Sci USA 91:4441–4445PubMedCrossRefGoogle Scholar
  78. 78.
    Reiter AK, Anthony TG, Anthony JC et al (2004) The mTOR signaling pathway mediates control of ribosomal protein mRNA translation in rat liver. Int J Biochem Cell Biol 36(11):2169–2179PubMedCrossRefGoogle Scholar
  79. 79.
    Mayer C, Zhao J, Yuan X et al (2004) mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev 18(4):423–434PubMedCrossRefGoogle Scholar
  80. 80.
    Jiang YP, Ballou LM, Lin RZ (2001) Rapamycin-insensitive regulation of 4e-BP1 in regenerating rat liver. J Biol Chem 276(14):10943–10951PubMedCrossRefGoogle Scholar
  81. 81.
    Palmes D, Zibert A, Budny T et al (2008) Impact of rapamycin on liver regeneration. Virchows Arch 452(5):545–557PubMedCrossRefGoogle Scholar
  82. 82.
    Marchesini G, Moscatiello S, Di Domizio S et al (2008) Obesity-associated liver disease. J Clin Endocrinol Metab 93(11 Suppl 1):S74–S80CrossRefGoogle Scholar
  83. 83.
    El-Serag HB, Hampel H, Javadi F (2006) The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 4(3):369–380PubMedCrossRefGoogle Scholar
  84. 84.
    Khamzina L, Veilleux A, Bergeron S et al (2005) Increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance. Endocrinology 146(3):1473–1481PubMedCrossRefGoogle Scholar
  85. 85.
    Le Bacquer O, Petroulakis E, Paglialunga S et al (2007) Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2. J Clin Invest 117(2):387–396PubMedCrossRefGoogle Scholar
  86. 86.
    Koketsu Y, Sakoda H, Fujishiro M et al (2008) Hepatic overexpression of a dominant negative form of raptor enhances Akt phosphorylation and restores insulin sensitivity in K/KAy mice. Am J Physiol Endocrinol Metab 294(4):E719–E725CrossRefGoogle Scholar
  87. 87.
    Prada PO, Hirabara SM, de Souza CT et al (2007) L-glutamine supplementation induces insulin resistance in adipose tissue and improves insulin signalling in liver and muscle of rats with diet-induced obesity. Diabetologia 50(9):1949–1959PubMedCrossRefGoogle Scholar
  88. 88.
    Calvert VS, Collantes R, Elariny H et al (2007) A systems biology approach to the pathogenesis of obesity-related nonalcoholic fatty liver disease using reverse phase protein microarrays for multiplexed cell signaling analysis. Hepatology 46(1):166–172PubMedCrossRefGoogle Scholar
  89. 89.
    Vinciguerra M, Veyrat-Durebex C, Moukil MA et al (2008) PTEN down-regulation by unsaturated fatty acids triggers hepatic steatosis via an NF-kappaBp65/mTOR-dependent mechanism. Gastroenterology 134(1):268–280PubMedCrossRefGoogle Scholar
  90. 90.
    Polesel J, Zucchetto A, Montella M et al (2008) The impact of obesity and diabetes mellitus on the risk of hepatocellular carcinoma. Ann Oncol 20:353–357PubMedCrossRefGoogle Scholar
  91. 91.
    Amarapurkar DN, Patel ND, Kamani PM (2008) Impact of diabetes mellitus on outcome of HCC. Ann Hepatol 7(2):148–151PubMedGoogle Scholar
  92. 92.
    Donadon V, Balbi M, Casarin P et al (2008) Association between hepatocellular carcinoma and type 2 diabetes mellitus in Italy: potential role of insulin. World J Gastroenterol 14(37):5695–5700PubMedCrossRefGoogle Scholar
  93. 93.
    Sahin F, Kannangai R, Adegbola O et al (2004) mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 10(24):8421–8425PubMedCrossRefGoogle Scholar
  94. 94.
    Sieghart W, Fuereder T, Schmid K et al (2007) Mammalian target of rapamycin pathway activity in hepatocellular ­carcinomas of patients undergoing liver transplantation. Transplantation 83(4):425–432PubMedCrossRefGoogle Scholar
  95. 95.
    Baba HA, Wohlschlaeger J, Cicinnati VR et al (2009) Phosphorylation of p70S6 kinase predicts overall survival in patients with clear margin-resected hepatocellular carcinoma. Liver Int 29:399–405PubMedCrossRefGoogle Scholar
  96. 96.
    Villanueva A, Chiang DY, Newell P et al (2008) Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastro­enterology 135:1972–1983, 1983.e1–11Google Scholar
  97. 97.
    Huynh H, Chow PK, Palanisamy N et al (2008) Beva­cizumab and rapamycin induce growth suppression in mouse models of hepatocellular carcinoma. J Hepatol 49(1):52–60PubMedCrossRefGoogle Scholar
  98. 98.
    Ladu S, Calvisi DF, Conner EA et al (2008) E2F1 inhibits c-Myc-driven apoptosis via PIK3CA/Akt/mTOR and COX-2 in a mouse model of human liver cancer. Gastro­enterology 135:1322–1332PubMedCrossRefGoogle Scholar
  99. 99.
    Huynh H, Chow KP, Soo KC et al (2008) RAD001 (everolimus) inhibits tumor growth in xenograft models of human hepatocellular carcinoma. J Cell Mol Med in pressGoogle Scholar
  100. 100.
    Piguet AC, Semela D, Keogh A et al (2008) Inhibition of mTOR in combination with doxorubicin in an experimental model of hepatocellular carcinoma. J Hepatol 49(1):78–87PubMedCrossRefGoogle Scholar
  101. 101.
    Wang Z, Zhou J, Fan J et al (2008) Effect of rapamycin alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma. Clin Cancer Res 14(16):5124–5130PubMedCrossRefGoogle Scholar
  102. 102.
    Tam KH, Yang ZF, Lau CK et al (2008) Inhibition of mTOR enhances chemosensitivity in hepatocellular carcinoma. Cancer Lett 273:201–209PubMedCrossRefGoogle Scholar
  103. 103.
    Lee JS, Chu IS, Mikaelyan A et al (2004) Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet 36(12):1306–1311PubMedCrossRefGoogle Scholar
  104. 104.
    Motzer RJ, Escudier B, Oudard S et al (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372(9637):449–456PubMedCrossRefGoogle Scholar
  105. 105.
    Awada A, Cardoso F, Fontaine C et al (2008) The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: results of a phase I study with pharmacokinetics. Eur J Cancer 44(1):84–91PubMedCrossRefGoogle Scholar
  106. 106.
    Yao JC, Phan AT, Chang DZ et al (2008) Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 26(26):4311–4318PubMedCrossRefGoogle Scholar
  107. 107.
    O’Donnell A, Faivre S, Burris HA 3rd et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 26(10): 1588–1595PubMedCrossRefGoogle Scholar
  108. 108.
    Tabernero J, Rojo F, Calvo E et al (2008) Dose- and ­schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor ­pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 26(10):1603–1610PubMedCrossRefGoogle Scholar
  109. 109.
    Kovarik JM, Kahan BD, Kaplan B et al (2001) Longitudinal assessment of everolimus in de novo renal transplant recipients over the first post-transplant year: pharmacokinetics, exposure-response relationships, and influence on cyclosporine. Clin Pharmacol Ther 69(1):48–56PubMedCrossRefGoogle Scholar
  110. 110.
    Tanaka C, O’Reilly T, Kovarik JM et al (2008) Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 26(10):1596–1602PubMedGoogle Scholar
  111. 111.
    Rizell M, Andersson M, Cahlin C et al (2008) Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer. Int J Clin Oncol 13(1):66–70PubMedCrossRefGoogle Scholar
  112. 112.
    Thompson JE, Thompson CB (2004) Putting the rap on Akt. J Clin Oncol 22(20):4217–4226PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Genome Research InstituteUniversity of CincinnatiCincinnatiUSA

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