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Current Status and Challenges Associated with Targeting mTOR for Cancer Therapy

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Abstract

The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in the regulation of cellular growth, survival, and proliferation. Inappropriate activation of PI3K/Akt/mTOR signaling can promote a cellular environment that is favorable for transformation. In fact, dysregulation of this pathway, as a result of genetic mutations and amplifications, is implicated in a variety of human cancers. Therefore, mTOR has emerged as a key target for the treatment of cancer, particularly in the treatment of tumors that exhibit increased mTOR signaling as a result of genetic lesions. The immunosuppressant sirolimus (rapamycin) directly inhibits mTOR activity and suppresses the growth of cancer cells in vitro and in vivo. As a result, a number of sirolimus derivatives have been developed as anti-cancer therapies, and these compounds are currently under investigation in phase I–III clinical trials. In this review, we summarize the use of sirolimus derivatives in clinical trials and address some of the challenges associated with targeting mTOR for the treatment of human cancer.

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References

  1. Bjornsti MA, Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004 May; 4(5): 335–48

    Article  PubMed  CAS  Google Scholar 

  2. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004 Aug 15; 18(16): 1926–45

    Article  PubMed  CAS  Google Scholar 

  3. Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med 2005 Aug; 11(8): 353–61

    Article  PubMed  CAS  Google Scholar 

  4. Oza AM, Elit L, Biagi J, et al. Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer [abstract no. 3003]. Annual Meeting, American Society of Clinical Oncology; 2006 Jun 2–6; Atlanta (GA)

  5. Le Tourneau C, Faivre S, Serova M, et al. mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work? Br J Cancer 2008 Oct 21;99(8): 1197–203

    Article  PubMed  CAS  Google Scholar 

  6. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007 May 31; 356(22): 2271–81

    Article  PubMed  CAS  Google Scholar 

  7. Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 1991 Aug 23; 253(5022): 905–9

    Article  PubMed  CAS  Google Scholar 

  8. Kunz J, Henriquez R, Schneider U, et al. Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 1993 May 7; 73(3): 585–96

    Article  PubMed  CAS  Google Scholar 

  9. Sabatini DM, Erdjument-Bromage H, Lui M, et al. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 1994 Jul 15; 78(1): 35–43

    Article  PubMed  CAS  Google Scholar 

  10. Brown EJ, Albers MW, Shin TB, et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 1994; 369: 756–8

    Article  PubMed  CAS  Google Scholar 

  11. Petroulakis E, Mamane Y, Le Bacquer O, et al. mTOR signaling: implications for cancer and anticancer therapy. Br J Cancer 2006 Jan 30; 94(2): 195–9

    Article  PubMed  CAS  Google Scholar 

  12. Yang Q, Guan KL. Expanding mTOR signaling. Cell Res 2007 Aug; 17(8): 666–81

    Article  PubMed  CAS  Google Scholar 

  13. Schalm SS, Fingar DC, Sabatini DM, et al. TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol 2003 May 13; 13(10): 797–806

    Article  PubMed  CAS  Google Scholar 

  14. Hara K, Maruki Y, Long X, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002 Jul 26; 110(2): 177–89

    Article  PubMed  CAS  Google Scholar 

  15. Schalm SS, Blenis J. Identification of a conserved motif required for mTOR signaling. Curr Biol 2002 Apr 16; 12(8): 632–9

    Article  PubMed  CAS  Google Scholar 

  16. Nojima H, Tokunaga C, Eguchi S, 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 May 2; 278(18): 15461–4

    Article  PubMed  CAS  Google Scholar 

  17. Vander Haar E, Lee SI, Bandhakavi S, et al. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 2007 Mar; 9(3): 316–23

    Article  PubMed  CAS  Google Scholar 

  18. Sancak Y, Thoreen CC, Peterson TR, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 2007 Mar 23; 25(6): 903–15

    Article  PubMed  CAS  Google Scholar 

  19. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 2006 Sep; 6(9): 729–34

    Article  PubMed  CAS  Google Scholar 

  20. Jacinto E, Facchinetti V, Liu D, et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 2006 Oct 6; 127(1): 125–37

    Article  PubMed  CAS  Google Scholar 

  21. Pestova TV, Lorsch JR, Hellen CUT. The mechanism of translation initiation in eukaryotes. In: Mathews MB, Sonenberg N, Hershey JWB, editors. Translational control in biology and medicine. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press, 2007: 87–128

    Google Scholar 

  22. Gingras AC, Raught B, Sonenberg N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 1999; 68: 913–63

    Article  PubMed  CAS  Google Scholar 

  23. Holcik M, Sonenberg N. Translational control in stress and apoptosis. Nat Rev Mol Cell Biol 2005 Apr; 6(4): 318–27

    Article  PubMed  CAS  Google Scholar 

  24. Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev 2001 Apr 1; 15(7): 807–26

    Article  PubMed  CAS  Google Scholar 

  25. Pause A, Belsham GJ, Gingras AC, et al. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function. Nature 1994 Oct 27; 371(6500): 762–7

    Article  PubMed  CAS  Google Scholar 

  26. Gingras AC, Gygi SP, Raught B, et al. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes Dev 1999 Jun 1; 13(11): 1422–37

    Article  PubMed  CAS  Google Scholar 

  27. Shahbazian D, Roux PP, Mieulet V, et al. The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. EMBO J 2006 Jun 21; 25(12): 2781–91

    Article  PubMed  CAS  Google Scholar 

  28. Richardson CJ, Broenstrup M, Fingar DC, et al. SKAR is a specific target of S6 kinase 1 in cell growth control. Curr Biol 2004 Sep 7; 14(17): 1540–9

    Article  PubMed  CAS  Google Scholar 

  29. Raught B, Gingras AC, Gygi SP, et al. Serum-stimulated, rapamycinsensitive phosphorylation sites in the eukaryotic translation initiation factor 4GI. EMBO J 2000 Feb 1; 19(3): 434–44

    Article  PubMed  CAS  Google Scholar 

  30. Raught B, Gingras AC, Sonenberg N. The target of rapamycin (TOR) proteins. Proc Natl Acad Sci U S A 2001 Jun 19; 98(13): 7037–44

    Article  PubMed  CAS  Google Scholar 

  31. Barnhart BC, Simon MC. Taking aim at translation for tumor therapy. J Clin Invest 2007 Sep; 117(9): 2385–8

    Article  PubMed  CAS  Google Scholar 

  32. Mamane Y, Petroulakis E, Rong L, et al. eIF4E: from translation to transformation. Oncogene 2004 Apr 19; 23(18): 3172–9

    Article  PubMed  CAS  Google Scholar 

  33. De Benedetti A, Graff JR. eIF-4E expression and its role in malignancies and metastases. Oncogene 2004 Apr 19; 23(18): 3189–99

    Article  PubMed  CAS  Google Scholar 

  34. Mamane Y, Petroulakis E, Martineau Y, et al. Epigenetic activation of a subset of mRNAs by eIF4E explains its effects on cell proliferation. PLoS ONE 2007; 2: e242

    Article  PubMed  CAS  Google Scholar 

  35. Lazaris-Karatzas A, Montine KS, Sonenberg N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′ cap. Nature 1990 Jun 7; 345(6275): 544–7

    Article  PubMed  CAS  Google Scholar 

  36. Lazaris-Karatzas A, Sonenberg N. The mRNA 5′ cap-binding protein, eIF-4E, cooperates with v-myc or E1A in the transformation of primary rodent fibroblasts. Mol Cell Biol 1992 Mar; 12(3): 1234–8

    PubMed  CAS  Google Scholar 

  37. Avdulov S, Li S, Michalek V, et al. Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell 2004 Jun; 5(6): 553–63

    Article  PubMed  CAS  Google Scholar 

  38. Ruggero D, Montanaro L, Ma L, et al. The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 2004 May; 10(5): 484–6

    Article  PubMed  CAS  Google Scholar 

  39. Wendel HG, De Stanchina E, Fridman JS, et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 2004 Mar 18; 428(6980): 332–7

    Article  PubMed  CAS  Google Scholar 

  40. De Benedetti A, Harris AL. eIF4E expression in tumors: its possible role in progression of malignancies. Int J Biochem Cell Biol 1999 Jan; 31(1): 59–72

    Article  PubMed  Google Scholar 

  41. Clemens MJ, Bommer UA. Translational control: the cancer connection. Int J Biochem Cell Biol 1999 Jan; 31(1): 1–23

    Article  PubMed  CAS  Google Scholar 

  42. Bauer C, Brass N, Diesinger I, et al. Overexpression of the eukaryotic translation initiation factor 4G (eIF4G-1) in squamous cell lung carcinoma. Int J Cancer 2002 Mar 10; 98(2): 181–5

    Article  PubMed  CAS  Google Scholar 

  43. Bauer C, Diesinger I, Brass N, et al. Translation initiation factor eIF-4G is immunogenic, overexpressed, and amplified in patients with squamous cell lung carcinoma. Cancer 2001 Aug 15; 92(4): 822–9

    Article  PubMed  CAS  Google Scholar 

  44. Eberle J, Krasagakis K, Orfanos CE. Translation initiation factor eIF-4A1 mRNA is consistently overexpressed in human melanoma cells in vitro. Int J Cancer 1997 May 2; 71(3): 396–401

    Article  PubMed  CAS  Google Scholar 

  45. Rousseau D, Gingras AC, Pause A, et al. The eIF4E-binding proteins 1 and 2 are negative regulators of cell growth. Oncogene 1996 Dec 5; 13(11): 2415–20

    PubMed  CAS  Google Scholar 

  46. Polunovsky VA, Gingras AC, Sonenberg N, et al. Translational control of the antiapoptotic function of Ras. J Biol Chem 2000 Aug 11; 275(32): 24776–80

    Article  PubMed  CAS  Google Scholar 

  47. Armengol G, Rojo F, Castellvi J, et al. 4E-Binding protein 1: a key molecular “funnel factor” in human cancer with clinical implications. Cancer Res 2007 Aug 15; 67(16): 7551–5

    Article  PubMed  CAS  Google Scholar 

  48. Castellvi J, Garcia A, Rojo F, et al. Phosphorylated 4E binding protein 1: a hallmark of cell signaling that correlates with survival in ovarian cancer. Cancer 2006 Oct 15; 107(8): 1801–11

    Article  PubMed  CAS  Google Scholar 

  49. Fumagalli S, Thomas G. S6 Phosphorylation and signal transduction. In: Sonenberg N, Hershey JWB, Mathews MB, editors. Translational control of gene expression. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press, 2000: 695–717

    Google Scholar 

  50. Shima H, Pende M, Chen Y, et al. Disruption of the p70(s6k)/p85(s6k) gene reveals a small mouse phenotype and a new functional S6 kinase. EMBO J 1998 Nov 16; 17(22): 6649–59

    Article  PubMed  CAS  Google Scholar 

  51. Dowling RJ, Zakikhani M, Fantus IG, et al. metformin inhibits mammalian target of rapamycin dependent translation initiation in breast cancer cells. Cancer Res 2007 Nov 15; 67(22): 10804–12

    Article  PubMed  CAS  Google Scholar 

  52. Inoki K, Li Y, Xu T, et al. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 2003 Aug 1; 17(15): 1829–34

    Article  PubMed  CAS  Google Scholar 

  53. Inoki K, Li Y, Zhu T, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002 Sep; 4(9): 648–57

    Article  PubMed  CAS  Google Scholar 

  54. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006 Aug; 5(8): 671–88

    Article  PubMed  CAS  Google Scholar 

  55. Fry MJ. Phosphoinositide 3-kinase signalling in breast cancer: how big a role might it play? Breast Cancer Res 2001; 3(5): 304–12

    Article  PubMed  CAS  Google Scholar 

  56. Philp AJ, Campbell IG, Leet C, et al. The phosphatidylinositol 3′-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res 2001 Oct 15; 61(20): 7426–9

    PubMed  CAS  Google Scholar 

  57. Luo J, Manning BD, Cantley LC. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 2003 Oct; 4(4): 257–62

    Article  PubMed  CAS  Google Scholar 

  58. Ikenoue T, Kanai F, Hikiba Y, et al. Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res 2005 Jun 1; 65(11): 4562–7

    Article  PubMed  CAS  Google Scholar 

  59. Podsypanina K, Ellenson LH, Nemes A, et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A 1999 Feb 16; 96(4): 1563–8

    Article  PubMed  CAS  Google Scholar 

  60. Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 2001 Aug 28; 98(18): 10314–9

    Article  PubMed  CAS  Google Scholar 

  61. Koksal IT, Dirice E, Yasar D, et al. The assessment of PTEN tumor suppressor gene in combination with Gleason scoring and serum PSA to evaluate progression of prostate carcinoma. Urol Oncol 2004 Jul–Aug; 22(4): 307–12

    Article  PubMed  CAS  Google Scholar 

  62. Kanamori Y, Kigawa J, Itamochi H, et al. Correlation between loss of PTEN expression and Akt phosphorylation in endometrial carcinoma. Clin Cancer Res 2001 Apr; 7(4): 892–5

    PubMed  CAS  Google Scholar 

  63. Di Cristofano A, Pandolfi PP. The multiple roles of PTEN in tumor suppression. Cell 2000 Feb 18; 100(4): 387–90

    Article  PubMed  Google Scholar 

  64. Stambolic V, Tsao MS, Macpherson D, et al. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/−mice. Cancer Res 2000 Jul 1; 60(13): 3605–11

    PubMed  CAS  Google Scholar 

  65. Di Cristofano A, Pesce B, Cordon-Cardo C, et al. Pten is essential for embryonic development and tumour suppression. Nat Genet 1998 Aug; 19(4): 348–55

    Article  PubMed  Google Scholar 

  66. Wang S, Gao J, Lei Q, et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 2003 Sep; 4(3): 209–21

    Article  PubMed  CAS  Google Scholar 

  67. Jaeschke A, Hartkamp J, Saitoh M, et al. Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent. J Cell Biol 2002 Oct 28; 159(2): 217–24

    Article  PubMed  CAS  Google Scholar 

  68. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003 Nov 26; 115(5): 577–90

    Article  PubMed  CAS  Google Scholar 

  69. Onda H, Lueck A, Marks PW, et al. Tsc2(+/−) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. J Clin Invest 1999 Sep; 104(6): 687–95

    Article  PubMed  CAS  Google Scholar 

  70. Kobayashi T, Minowa O, Kuno J, et al. Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice. Cancer Res 1999 Mar 15; 59(6): 1206–11

    PubMed  CAS  Google Scholar 

  71. Woods A, Johnstone SR, Dickerson K, et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 2003 Nov 11; 13(22): 2004–8

    Article  PubMed  CAS  Google Scholar 

  72. Hawley SA, Boudeau J, Reid JL, et al. Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2003; 2(4): 28

    Article  PubMed  Google Scholar 

  73. Kahn BB, Alquier T, Carling D, et al. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 2005 Jan; 1(1): 15–25

    Article  PubMed  CAS  Google Scholar 

  74. Shaw RJ, Bardeesy N, Manning BD, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 2004 Jul; 6(1): 91–9

    Article  PubMed  CAS  Google Scholar 

  75. Hemminki A, Markie D, Tomlinson I, et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 1998 Jan 8; 391(6663): 184–7

    Article  PubMed  CAS  Google Scholar 

  76. Bardeesy N, Sinha M, Hezel AF, et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 2002 Sep 12; 419(6903): 162–7

    Article  PubMed  CAS  Google Scholar 

  77. Weinstein IB. Cancer: addiction to oncogenes —the Achilles heal of cancer. Science 2002 Jul 5; 297(5578): 63–4

    Article  PubMed  CAS  Google Scholar 

  78. Easton JB, Houghton PJ. mTOR and cancer therapy. Oncogene 2006 Oct 16; 25(48): 6436–46

    Article  PubMed  CAS  Google Scholar 

  79. Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic: I, taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 1975 Oct; 28(10): 721–6

    Article  CAS  Google Scholar 

  80. Choi J, Chen J, Schreiber SL, et al. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 1996 Jul 12; 273(5272): 239–42

    Article  PubMed  CAS  Google Scholar 

  81. Chiang GG, Abraham RT. Targeting the mTOR signaling network in cancer. Trends Mol Med 2007 Oct; 13(10): 433–42

    Article  PubMed  CAS  Google Scholar 

  82. Oshiro N, Yoshino K, Hidayat S, et al. Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function. Genes Cells 2004 Apr; 9(4): 359–66

    Article  PubMed  CAS  Google Scholar 

  83. Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004 Nov; 6(11): 1122–8

    Article  PubMed  CAS  Google Scholar 

  84. Wu L, Birle DC, Tannock IF. Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells and xenografts. Cancer Res 2005 Apr 1; 65(7): 2825–31

    Article  PubMed  CAS  Google Scholar 

  85. Mosley JD, Poirier JT, Seachrist DD, et al. Rapamycin inhibits multiple stages of c-Neu/ErbB2 induced tumor progression in a transgenic mouse model of HER2-positive breast cancer. Mol Cancer Ther 2007 Aug; 6(8): 2188–97

    Article  PubMed  CAS  Google Scholar 

  86. Yu K, Toral-Barza L, Discafani C, et al. 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 Sep; 8(3): 249–58

    Article  PubMed  Google Scholar 

  87. Noh WC, Mondesire WH, Peng J, et al. Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res 2004 Feb 1; 10(3): 1013–23

    Article  PubMed  CAS  Google Scholar 

  88. Beretta L, Gingras AC, Svitkin YV, et al. Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J 1996 Feb 1; 15(3): 658–64

    PubMed  CAS  Google Scholar 

  89. Grolleau A, Bowman J, Pradet-Balade B, et al. Global and specific translational control by rapamycin in T cells uncovered by microarrays and proteomics. J Biol Chem 2002 Jun 21; 277(25): 22175–84

    Article  PubMed  CAS  Google Scholar 

  90. Huang S, Liu LN, Hosoi H, et al. p53/p21(CIP1) cooperate in enforcing rapamycin-induced G(1) arrest and determine the cellular response to rapamycin. Cancer Res 2001 Apr 15; 61(8): 3373–81

    PubMed  CAS  Google Scholar 

  91. Abraham RT, Eng CH. Mammalian target of rapamycin as a therapeutic target in oncology. Expert Opin Ther Targets 2008 Feb; 12(2): 209–22

    Article  PubMed  CAS  Google Scholar 

  92. Tsang CK, Qi H, Liu LF, et al. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today 2007 Feb; 12(3-4): 112–24

    Article  PubMed  CAS  Google Scholar 

  93. Hidalgo M, Buckner JC, Erlichman C, et al. A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 2006 Oct 1; 12(19): 5755–63

    Article  PubMed  CAS  Google Scholar 

  94. Raymond E, Alexandre J, Faivre S, et al. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 2004 Jun 15; 22(12): 2336–47

    Article  PubMed  CAS  Google Scholar 

  95. Chan S, Scheulen ME, Johnston 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 Aug 10; 23(23): 5314–22

    Article  PubMed  CAS  Google Scholar 

  96. Atkins MB, Hidalgo M, Stadler WM, 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 Mar 1; 22(5): 909–18

    Article  PubMed  CAS  Google Scholar 

  97. Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005 Aug 10; 23(23): 5347–56

    Article  PubMed  CAS  Google Scholar 

  98. O’Donnell A, Faivre S, Judson I, 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 pharmaco-dynamic (PD) endpoints in patients with solid tumours [abstract no. A803]. Annual Meeting, American Society of Clinical Oncology; 2003 May 31–Jun 3; Chicago (IL)

  99. Boulay A, Zumstein-Mecker S, Stephan C, 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 Jan 1; 64(1): 252–61

    Article  PubMed  CAS  Google Scholar 

  100. Smolewski P. Recent developments in targeting the mammalian target of rapamycin (mTOR) kinase pathway. Anticancer Drugs 2006 Jun; 17(5): 487–94

    Article  PubMed  CAS  Google Scholar 

  101. Yee KW, Zeng Z, Konopleva M, et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2006 Sep 1; 12(17): 5165–73

    Article  PubMed  CAS  Google Scholar 

  102. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008 Aug 9; 372(9637): 449–56

    Article  PubMed  CAS  Google Scholar 

  103. Mita MM, Mita AC, Chu QS, et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 2008 Jan 20; 26(3): 361–7

    Article  PubMed  CAS  Google Scholar 

  104. Iwenofu OH, Lackman RD, Staddon AP, et al. Phospho-S6 ribosomal protein: a potential new predictive sarcoma marker for targeted mTOR therapy. Mod Pathol 2008 Mar; 21(3): 231–7

    Article  PubMed  CAS  Google Scholar 

  105. Sarbassov DD, Guertin DA, Ali SM, et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005 Feb 18; 307(5712): 1098–101

    Article  PubMed  CAS  Google Scholar 

  106. Bayascas JR, Alessi DR. Regulation of Akt/PKB Ser473 phosphorylation. Mol Cell 2005 Apr 15; 18(2): 143–5

    Article  PubMed  CAS  Google Scholar 

  107. Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006 Apr 21; 22(2): 159–68

    Article  PubMed  CAS  Google Scholar 

  108. Manning BD. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 2004 Nov 8; 167(3)

  109. Shah OJ, Wang Z, Hunter T. Inappropriate activation of the TSC/ Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 2004 Sep 21; 14(18): 1650–6

    Article  PubMed  CAS  Google Scholar 

  110. Harrington LS, Findlay GM, Gray A, et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 2004 Jul 19;166(2): 213-23

  111. Greene MW, Sakaue H, Wang L, et al. Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by serine 312 phosphorylation. J Biol Chem 2003 Mar 7; 278(10): 8199–211

    Article  PubMed  CAS  Google Scholar 

  112. O’Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006 Feb 1;66(3): 1500–8

    Article  PubMed  CAS  Google Scholar 

  113. Zhang H, Bajraszewski N, Wu E, et al. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest 2007 Mar; 117(3): 730–8

    Article  PubMed  CAS  Google Scholar 

  114. Buck E, Eyzaguirre A, Brown E, et al. Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol Cancer Ther 2006 Nov; 5(11): 2676–84

    Article  PubMed  CAS  Google Scholar 

  115. Skeen JE, Bhaskar PT, Chen CC, et al. Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner. Cancer Cell 2006 Oct; 10(4): 269–80

    Article  PubMed  CAS  Google Scholar 

  116. Wang MY, Lu KV, Zhu S, et al. Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells. Cancer Res 2006 Aug 15; 66(16): 7864–9

    Article  PubMed  CAS  Google Scholar 

  117. Birle DC, Hedley DW. Signaling interactions of rapamycin combined with erlotinib in cervical carcinoma xenografts. Mol Cancer Ther 2006 Oct; 5(10): 2494–502

    Article  PubMed  CAS  Google Scholar 

  118. Azzariti A, Porcelli L, Gatti G, et al. Synergic antiproliferative and antiangiogenic effects of EGFR and mTor inhibitors on pancreatic cancer cells. Biochem Pharmacol 2008 Mar 1; 75(5): 1035–44

    Article  PubMed  CAS  Google Scholar 

  119. Doherty L, Gigas DC, Kesari S, et al. Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. Neurology 2006 Jul 11; 67(1): 156–8

    Article  PubMed  CAS  Google Scholar 

  120. Milton DT, Riely GJ, Azzoli CG, et al. Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer. Cancer 2007 Aug 1; 110(3): 599–605

    Article  PubMed  CAS  Google Scholar 

  121. Beuvink I, Boulay A, Fumagalli S, et al. The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 2005 Mar 25; 120(6): 747–59

    Article  PubMed  CAS  Google Scholar 

  122. Mondesire WH, Jian W, Zhang H, et al. Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res 2004 Oct 15; 10(20): 7031–42

    Article  PubMed  CAS  Google Scholar 

  123. Raje N, Kumar S, Hideshima T, et al. Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood 2004 Dec 15; 104(13): 4188–93

    Article  PubMed  CAS  Google Scholar 

  124. Mohi MG, Boulton C, Gu TL, et al. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci U S A 2004 Mar 2; 101(9): 3130–5

    Article  PubMed  CAS  Google Scholar 

  125. de Graffenried LA, Friedrichs WE, Russell DH, et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res 2004 Dec 1; 10(23): 8059–67

    Article  Google Scholar 

  126. Awada A, Cardoso F, Fontaine C, et al. 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 2008 Jan; 44(1): 84–91

    Article  PubMed  CAS  Google Scholar 

  127. Tokunaga E, Kimura Y, Mashino K, et al. Activation of PI3K/Akt signaling and hormone resistance in breast cancer. Breast Cancer 2006; 13(2): 137–44

    Article  PubMed  Google Scholar 

  128. Shinohara ET, Cao C, Niermann K, et al. Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene 2005 Aug 18; 24(35): 5414–22

    Article  PubMed  CAS  Google Scholar 

  129. Podsypanina K, Lee RT, Politis C, et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/−mice. Proc Natl Acad Sci U S A 2001 Aug 28; 98(18): 10320–5

    Article  PubMed  CAS  Google Scholar 

  130. Shi Y, Gera J, Hu L, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res 2002 Sep 1; 62(17): 5027–34

    PubMed  CAS  Google Scholar 

  131. Uegaki K, Kanamori Y, Kigawa J, et al. PTEN-positive and phosphorylated-Akt-negative expression is a predictor of survival for patients with advanced endometrial carcinoma. Oncol Rep 2005 Aug; 14(2): 389–92

    PubMed  CAS  Google Scholar 

  132. Tashiro H, Blazes MS, Wu R, et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res 1997 Sep 15; 57(18): 3935–40

    PubMed  CAS  Google Scholar 

  133. Wendel HG, Malina A, Zhao Z, et al. Determinants of sensitivity and resistance to rapamycin-chemotherapy drug combinations in vivo. Cancer Res 2006 Aug 1; 66(15): 7639–46

    Article  PubMed  CAS  Google Scholar 

  134. Galanis E, Buckner JC, Maurer MJ, et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 2005 Aug 10; 23(23): 5294–304

    Article  PubMed  CAS  Google Scholar 

  135. Margolin K, Longmate J, Baratta T, et al. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer 2005 Sep 1; 104(5): 1045–8

    Article  PubMed  CAS  Google Scholar 

  136. Chang SM, Wen P, Cloughesy T, et al. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 2005 Aug; 23(4): 357–61

    Article  PubMed  CAS  Google Scholar 

  137. Cho D, Signoretti S, Regan M, et al. The role of mammalian target of rapamycin inhibitors in the treatment of advanced renal cancer. Clin Cancer Res 2007 Jan 15; 13 (2 Pt 2): 758s–63s

    Article  PubMed  CAS  Google Scholar 

  138. Dilling MB, Germain GS, Dudkin L, 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 Apr 19; 277(16): 13907–17

    Article  PubMed  CAS  Google Scholar 

  139. Aguirre D, Boya P, Bellet D, et al. Bcl-2 and CCND1/CDK4 expression levels predict the cellular effects of mTOR inhibitors in human ovarian carcinoma. Apoptosis 2004 Nov; 9(6): 797–805

    Article  PubMed  CAS  Google Scholar 

  140. Feldman ME, Apsel B, Uotila A, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009 Feb 10; 7(2): e38

    Article  PubMed  CAS  Google Scholar 

  141. Thoreen CC, Kang SA, Chang JW, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 2009 Mar 20; 284(12): 8023–32

    Article  PubMed  CAS  Google Scholar 

  142. Howes AL, Chiang GG, Lang ES, et al. The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures. Mol Cancer Ther 2007 Sep; 6(9): 2505–14

    Article  PubMed  CAS  Google Scholar 

  143. Billottet C, Grandage VL, Gale RE, et al. A selective inhibitor of the p110delta isoform of PI 3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP 16. Oncogene 2006 Oct 26; 25(50): 6648–59

    Article  PubMed  CAS  Google Scholar 

  144. Schultz RM, Merriman RL, Andis SL, et al. In vitro and in vivo antitumor activity of the phosphatidylinositol-3-kinase inhibitor, wortmannin. Anticancer Res 1995 Jul–Aug; 15(4): 1135–9

    PubMed  CAS  Google Scholar 

  145. Ward S, Sotsios Y, Dowden J, et al. Therapeutic potential of phosphoinositide 3-kinase inhibitors. Chem Biol 2003 Mar; 10(3): 207–13

    Article  PubMed  CAS  Google Scholar 

  146. Fan QW, Knight ZA, Goldenberg DD, et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 2006 May; 9(5): 341–9

    Article  PubMed  CAS  Google Scholar 

  147. DeFeo-Jones D, Barnett SF, Fu S, et al. Tumor cell sensitization to apoptotic stimuli by selective inhibition of specific Akt/PKB family members. Mol Cancer Ther 2005 Feb; 4(2): 271–9

    PubMed  CAS  Google Scholar 

  148. Rattan R, Giri S, Singh AK, et al. 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase. J Biol Chem 2005 Nov 25; 280(47): 39582–93

    Article  PubMed  CAS  Google Scholar 

  149. Zakikhani M, Dowling R, Fantus IG, et al. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006 Nov 1; 66(21): 10269–73

    Article  PubMed  CAS  Google Scholar 

  150. Buzzai M, Jones RG, Amaravadi RK, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 2007 Jul 15; 67(14): 6745–52

    Article  PubMed  CAS  Google Scholar 

  151. Evans JM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005 Jun 4; 330(7503): 1304–5

    Article  PubMed  Google Scholar 

  152. Pollak M. Insulin and insulin-like growth factor signaling in neoplasia. Nat Rev Cancer 2008 Dec; 8: 915–28

    Article  PubMed  CAS  Google Scholar 

  153. Ballou LM, Selinger ES, Choi JY, et al. Inhibition ofmammalian target of rapamycin signaling by 2-(morpholin-1-yl)pyrimido[2,1-alpha]isoquinolin-4-one. J Biol Chem 2007 Aug 17; 282(33): 24463–70

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by a grant to Michael Pollak and Nahum Sonenberg from the Canadian Breast Cancer Research Alliance. Nahum Sonenberg is a Howard Hughes Medical Institute International Research Scholar and a James McGill Professor. Ryan Dowling is supported by a Research Studentship provided by the Terry Fox Foundation through the National Cancer Institute of Canada. The authors thank Colin Lister for his excellent technical assistance. The authors have no conflicts of interest that relate to the content of this review article.

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  1. Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, 1160 Pine Avenue West, Room 615, Montreal, Quebec, Canada, H3A 1A3

    Ryan J.O. Dowling &  Nahum Sonenberg

  2. Department of Oncology, McGill University, and Cancer Prevention Centre, Jewish General Hospital, Montreal, Quebec, Canada

    Michael Pollak

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  1. Ryan J.O. Dowling
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  2. Michael Pollak
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Correspondence to Nahum Sonenberg.

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Dowling, R.J., Pollak, M. & Sonenberg, N. Current Status and Challenges Associated with Targeting mTOR for Cancer Therapy. BioDrugs 23, 77–91 (2009). https://doi.org/10.2165/00063030-200923020-00002

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