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mTOR and Cancer Therapy: General Principles

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mTOR Pathway and mTOR Inhibitors in Cancer Therapy

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

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Abstract

mTOR (mammalian target of rapamycin) is a serine/threonine kinase that plays a pivotal role in coordinating cell cycle progression in response to intracellular and extracellular queues. Pathways upstream of mTORC1, a complex that controls cap-dependent translation, are dysregulated in most human cancers. Dysregulation downstream of mTORC1 also occurs in many human cancers. In model systems activation of mTORC1 increases the incidence and penetrance of cancer, as does overexpression of eIF4E, the RNA cap-binding protein that is regulated by mTORC1 signaling. The mTORC1 complex regulates translation of cell cycle regulators, angiogenic factors, as well as factors that control cell motility. However, the role of the mTORC2 complex is less well defined, but activation of mTORC2, and phosphorylation of at least one substrate AKT(S473), may activate survival pathways. Taken together, there is compelling data to support development of cancer therapies that abrogate mTORC1 and/or mTORC2 signaling either directly or at sites upstream or downstream of this complex.

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Notes

  1. 1.

    Oza et al. [23].

  2. 2.

    Cam et al. [60].

References

  1. Sehgal SN, Baker H, Vezina C (1975) Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo) 28:727–732

    Article  CAS  Google Scholar 

  2. Calne RY, Collier DS, Lim S et al (1989) Rapamycin for immunosuppression in organ allografting. Lancet 2:227

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  6. Weinstein IB, Joe AK (2006) Mechanisms of disease: oncogene addiction – a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 3:448–457

    Article  PubMed  CAS  Google Scholar 

  7. Engelman JA, Janne PA (2008) Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 14:2895–2899

    Article  PubMed  Google Scholar 

  8. Engelman JA, Zejnullahu K, Mitsudomi T et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043

    Article  PubMed  CAS  Google Scholar 

  9. Laurent-Puig P, Taieb J (2008) Lessons from Tarceva in pancreatic cancer: where are we now, and how should future trials be designed in pancreatic cancer? Curr Opin Oncol 20: 454–458

    Article  PubMed  Google Scholar 

  10. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619

    Article  PubMed  CAS  Google Scholar 

  11. Yuan TL, Cantley LC (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27:5497–5510

    Article  PubMed  CAS  Google Scholar 

  12. Oda K, Stokoe D, Taketani Y, McCormick F (2005) High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res 65:10669–10673

    Article  PubMed  CAS  Google Scholar 

  13. Muller CI, Miller CW, Hofmann WK et al (2007) Rare mutations of the PIK3CA gene in malignancies of the hematopoietic system as well as endometrium, ovary, prostate and osteosarcomas, and discovery of a PIK3CA pseudogene. Leuk Res 31:27–32

    Article  PubMed  CAS  Google Scholar 

  14. Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL (1998) The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci USA 95:15587–15591

    Article  PubMed  CAS  Google Scholar 

  15. Cantley LC, Neel BG (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 96:4240–4245

    Article  PubMed  CAS  Google Scholar 

  16. Stambolic V, Suzuki A, de la Pompa JL et al (1998) Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95:29–39

    Article  PubMed  CAS  Google Scholar 

  17. Sansal I, Sellers WR (2004) The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 22:2954–2963

    Article  PubMed  CAS  Google Scholar 

  18. Simpson L, Parsons RPTEN (2001) life as a tumor suppressor. Exp Cell Res 264:29–41

    Article  PubMed  CAS  Google Scholar 

  19. Podsypanina K, Lee RT, Politis C et al (2001) An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/– mice. Proc Natl Acad Sci USA 98:10320–10325

    Article  PubMed  CAS  Google Scholar 

  20. Wendel HG, De Stanchina E, Fridman JS et al (2004) Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428:332–337

    Article  PubMed  CAS  Google Scholar 

  21. Yu K, Toral-Barza L, Discafani C et al (2001) mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 8:249–258

    Article  PubMed  Google Scholar 

  22. Neshat MS, Mellinghoff IK, Tran C et al (2001) Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 98:10314–10319

    Article  PubMed  CAS  Google Scholar 

  23. Oza AM, Elit L, Biagi J et al (2006) Molecular correlates associated with a phase II study of temsirolimus (CCI-779). J Clin Oncol ASCO Ann Meet Proc 24:18S (abstract 3003)

    Google Scholar 

  24. Cloughesy TF, Yoshimoto K, Nghiemphu P et al (2008) Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 5:e8

    Article  PubMed  CAS  Google Scholar 

  25. Parsons DW, Wang TL, Samuels Y et al (2005) Colorectal cancer: mutations in a signalling pathway. Nature 436:792

    Article  PubMed  CAS  Google Scholar 

  26. Liu LZ, Zhou XD, Qian G, Shi X, Fang J, Jiang BH (2007) AKT1 amplification regulates cisplatin resistance in human lung cancer cells through the mammalian target of rapamycin/p70S6K1 pathway. Cancer Res 67:6325–6332

    Article  PubMed  CAS  Google Scholar 

  27. Knobbe CB, Reifenberger G (2003) Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3′-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. Brain Pathol 13:507–518

    Article  PubMed  CAS  Google Scholar 

  28. Staal SP (1987) Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Natl Acad Sci USA 84:5034–5037

    Article  PubMed  CAS  Google Scholar 

  29. Carpten JD, Faber AL, Horn C et al (2007) A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448:439–444

    Article  PubMed  CAS  Google Scholar 

  30. Liu L, Cash TP, Jones RG, Keith B, Thompson CB, Simon MC (2006) Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell 21:521–531

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  32. Yeung RS, Xiao G, Jin F, Lee W, Testa JR, Knudson AG (1994) Predisposition to Renal Carcinoma in the Eker Rat is Determined by Germ-Line Mutation of the Tuberous Sclerosis 2 (TSC2) Gene. PNAS 91:11413–11416

    Article  PubMed  CAS  Google Scholar 

  33. Kwiatkowski DJ (2003) Tuberous Sclerosis: from Tubers to mTOR. Ann Hum Genet 67:87–96

    Article  PubMed  CAS  Google Scholar 

  34. Ehninger D, Han S, Shilyansky C et al (2008) Reversal of learning deficits in a Tsc2+/– mouse model of tuberous sclerosis. Nat Med 14:843–848

    Article  PubMed  CAS  Google Scholar 

  35. Giardiello FM, Welsh SB, Hamilton SR et al (1987) Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med 316:1511–1514

    Article  PubMed  CAS  Google Scholar 

  36. Shaw RJ, Bardeesy N, Manning BD et al (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6:91–99

    Article  PubMed  CAS  Google Scholar 

  37. Nardella C, Chen Z, Salmena L et al (2008) Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events. Genes Dev 22:2172–2177

    Article  PubMed  CAS  Google Scholar 

  38. Mavrakis KJ, Zhu H, Silva RL et al (2008) Tumorigenic activity and therapeutic inhibition of Rheb GTPase. Genes Dev 22:2178–2188

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  41. Wang S, Lloyd RV, Hutzler MJ et al (2001) Expression of eukaryotic translation initiation factors 4E and 2alpha correlates with the progression of thyroid carcinoma. Thyroid 11:1101–1107

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  43. Rosenwald IB, Chen JJ, Wang S, Savas L, London IM, Pullman J (1999) Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. Oncogene 18:2507–2517

    Article  PubMed  CAS  Google Scholar 

  44. Li BD, Gruner JS, Abreo F et al (2002) Prospective study of eukaryotic initiation factor 4E protein elevation and breast cancer outcome. Ann Surg 235:732–738; discussion 8–9

    Article  PubMed  Google Scholar 

  45. Crew JP, Fuggle S, Bicknell R, Cranston DW, de Benedetti A, Harris AL (2000) 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 82:161–166

    Article  PubMed  CAS  Google Scholar 

  46. Scott PA, Smith K, Poulsom R, De Benedetti A, Bicknell R, Harris AL (1998) Differential expression of vascular endothelial growth factor mRNA vs protein isoform expression in human breast cancer and relationship to eIF-4E. Br J Cancer 77:2120–2128

    Article  PubMed  CAS  Google Scholar 

  47. Ruggero D, Montanaro L, Ma L et al (2004) The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 10:484–486

    Article  PubMed  CAS  Google Scholar 

  48. Mavrakis KJ, Zhu H, Silva RL, et al (2008) Tumorigenic activity and therapeutic inhibition of Rheb GTPase. Genes Dev 22:2178–2188

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  51. Martin ME, Perez MI, Redondo C, Alvarez MI, Salinas M, Fando JL (2000) 4E binding protein 1 expression is inversely correlated to the progression of gastrointestinal cancers. Int J Biochem Cell Biol 32:633–642

    Article  PubMed  CAS  Google Scholar 

  52. Dilling MB, Germain GS, Dudkin L et al (2002) 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 277:13907–13917

    Article  PubMed  CAS  Google Scholar 

  53. Avdulov S, Li S, Michalek V et al (2004) Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell 5:553–563

    Article  PubMed  CAS  Google Scholar 

  54. Lazaris-Karatzas A, Smith MR, Frederickson RM et al (1992) Ras mediates translation initiation factor 4E-induced malignant transformation. Genes Dev 6:1631–1642

    Article  PubMed  CAS  Google Scholar 

  55. Lazaris-Karatzas A, Sonenberg N (1992) The mRNA 5′ cap-binding protein, eIF-4E, cooperates with v-myc or E1A in the transformation of primary rodent fibroblasts. Mol Cell Biol 12:1234–1238

    PubMed  CAS  Google Scholar 

  56. Mao JH, Kim IJ, Wu D et al (2008) FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression. Science 321:1499–1502

    Article  PubMed  CAS  Google Scholar 

  57. Feng Z, Zhang H, Levine AJ, Jin S (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 102:8204–8209

    Article  PubMed  CAS  Google Scholar 

  58. Budanov AV, Karin M (2008) p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134:451–460

    Article  PubMed  CAS  Google Scholar 

  59. Lee CH, Inoki K, Karbowniczek M et al (2007) Constitutive mTOR activation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53. EMBO J 26:4812–4823

    Article  PubMed  CAS  Google Scholar 

  60. Cam H et al (submitted) mTORC1 signalling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α

    Google Scholar 

  61. Mungamuri SK, Yang X, Thor AD, Somasundaram K (2006) Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res 66:4715–4724

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  63. Thimmaiah KN, Easton J, Huang S et al (2003) Insulin-like growth factor I-mediated protection from rapamycin-induced apoptosis is independent of Ras-Erk1-Erk2 and phosphatidylinositol 3′-kinase-Akt signaling pathways. Cancer Res 63:364–374

    PubMed  CAS  Google Scholar 

  64. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484

    Article  PubMed  CAS  Google Scholar 

  65. Sabatini DM (2006) mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 6:729–734

    Article  PubMed  CAS  Google Scholar 

  66. Liu L, Chen L, Chung J, Huang S (2008) Rapamycin inhibits F-actin reorganization and phosphorylation of focal adhesion proteins. Oncogene 27:4998–5010

    Article  PubMed  CAS  Google Scholar 

  67. Liu L, Li F, Cardelli JA, Martin KA, Blenis J, Huang S (2006) Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways. Oncogene 25:7029–7040

    Article  PubMed  CAS  Google Scholar 

  68. Jiang X, Zhu S, Panetti TS, Bromberg ME (2008) Formation of tissue factor-factor VIIa-factor Xa complex induces activation of the mTOR pathway which regulates migration of human breast cancer cells. Thromb Haemost 100:127–133

    PubMed  CAS  Google Scholar 

  69. Masri J, Bernath A, Martin J et al (2007) mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res 67:11712–11720

    Article  PubMed  CAS  Google Scholar 

  70. Holt RU, Fagerli UM, Baykov V et al (2008) Hepatocyte growth factor promotes migration of human myeloma cells. Haematologica 93:619–622

    Article  PubMed  CAS  Google Scholar 

  71. Dada S, Demartines N, Dormond O (2008) mTORC2 regulates PGE2-mediated endothelial cell survival and migration. Biochem Biophys Res Commun 372:875–879

    Article  PubMed  CAS  Google Scholar 

  72. Hernandez-Negrete I, Carretero-Ortega J, Rosenfeldt H et al (2007) P-Rex1 links mammalian target of rapamycin signaling to Rac activation and cell migration. J Biol Chem 282:23708–23715

    Article  PubMed  CAS  Google Scholar 

  73. Ouyang W, Li J, Shi X, Costa M, Huang C (2005) Essential role of PI-3 K, ERKs and calcium signal pathways in nickel-induced VEGF expression. Mol Cell Biochem 279:35–43

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  75. Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL (2001) 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 21:3995–4004

    Article  PubMed  CAS  Google Scholar 

  76. Zhong H, Chiles K, Feldser D et al (2000) 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 60:1541–1545

    PubMed  CAS  Google Scholar 

  77. Yu Y, Sato JD (1999) MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase mediate the mitogenic response of human endothelial cells to vascular endothelial growth factor. J Cell Physiol 178:235–246

    Article  PubMed  CAS  Google Scholar 

  78. Hudson CC, Liu M, Chiang GG et al (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22:7004–7014

    Article  PubMed  CAS  Google Scholar 

  79. Brugarolas J, Lei K, Hurley RL et al (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18:2893–2904

    Article  PubMed  CAS  Google Scholar 

  80. Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG Jr (2003) TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4:147–158

    Article  PubMed  CAS  Google Scholar 

  81. Guba M, Graeb C, Jauch KW, Geissler EK (2004) Pro- and anti-cancer effects of immunosuppressive agents used in organ transplantation. Transplantation 77:1777–1782

    Article  PubMed  CAS  Google Scholar 

  82. Guba M, Koehl GE, Neppl E et al (2005) Dosing of rapamycin is critical to achieve an optimal antiangiogenic effect against cancer. Transpl Int 18:89–94

    Article  PubMed  CAS  Google Scholar 

  83. Guba M, von Breitenbuch P, Steinbauer M et al (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8:128–135

    Article  PubMed  CAS  Google Scholar 

  84. Barilli A, Visigalli R, Sala R et al (2008) In human endothelial cells rapamycin causes mTORC2 inhibition and impairs cell viability and function. Cardiovasc Res 78:563–571

    Article  PubMed  CAS  Google Scholar 

  85. Kurmasheva RT, Harwood FC, Houghton PJ (2007) Differential regulation of vascular endothelial growth factor by Akt and mammalian target of rapamycin inhibitors in cell lines derived from childhood solid tumors. Mol Cancer Ther 6:1620–1628

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  87. Zhou J, Wulfkuhle J, Zhang H et al (2007) Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci USA 104:16158–16163

    Article  PubMed  CAS  Google Scholar 

  88. Yilmaz OH, Valdez R, Theisen BK et al (2006) Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441:475–482

    Article  PubMed  CAS  Google Scholar 

  89. Yilmaz OH, Morrison SJ (2008) The PI-3kinase pathway in hematopoietic stem cells and leukemia-initiating cells: a mechanistic difference between normal and cancer stem cells. Blood Cells Mol Dis 41:73–76

    Article  PubMed  CAS  Google Scholar 

  90. Jiang BH, Liu LZ (2008) Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment. Drug Resist Updat 11:63–76

    Article  PubMed  CAS  Google Scholar 

  91. Opel D, Westhoff MA, Bender A, Braun V, Debatin KM, Fulda S (2008) Phosphatidylinositol 3-kinase inhibition broadly sensitizes glioblastoma cells to death receptor- and drug-induced apoptosis. Cancer Res 68:6271–6280

    Article  PubMed  CAS  Google Scholar 

  92. Brognard J, Clark AS, Ni Y, Dennis PA (2001) Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 61:3986–3997

    PubMed  CAS  Google Scholar 

  93. Clark AS, West K, Streicher S, Dennis PA (2002) Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 1:707–717

    PubMed  CAS  Google Scholar 

  94. Mabuchi S, Ohmichi M, Kimura A et al (2002) Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel. J Biol Chem 277:33490–33500

    Article  PubMed  CAS  Google Scholar 

  95. Plas DR, Talapatra S, Edinger AL, Rathmell JC, Thompson CB (2001) Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology. J Biol Chem 276:12041–12048

    Article  PubMed  CAS  Google Scholar 

  96. Edinger AL, Thompson CB (2002) Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol Biol Cell 13:2276–2288

    Article  PubMed  CAS  Google Scholar 

  97. VanderWeele DJ, Zhou R, Rudin CM (2004) Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin. Mol Cancer Ther 3:1605–1613

    PubMed  CAS  Google Scholar 

  98. Dickson PV, Hamner JB, Sims TL et al (2007) Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res 13:3942–3950

    Article  PubMed  CAS  Google Scholar 

  99. Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7:987–989

    Article  PubMed  CAS  Google Scholar 

  100. Houghton PJ, Morton CL, Gorlick R, et al (2010) Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. Mol Cancer Ther 9: 101–112

    Google Scholar 

  101. Shen C, Lancaster CS, Shi B, Guo H, Thimmaiah P, Bjornsti MA (2007) TOR signaling is a determinant of cell survival in response to DNA damage. Mol Cell Biol 27:7007–7017

    Article  PubMed  CAS  Google Scholar 

  102. Wu C, Wangpaichitr M, Feun L et al (2005) Overcoming cisplatin resistance by mTOR inhibitor in lung cancer. Mol Cancer 4:25

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  104. Thallinger C, Poeppl W, Pratscher B et al (2007) CCI-779 plus cisplatin is highly effective against human melanoma in a SCID mouse xenotransplantation model. Pharmacology 79:207–213

    Article  PubMed  CAS  Google Scholar 

  105. Beuvink I, Boulay A, Fumagalli S et al (2005) The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 120:747–759

    Article  PubMed  CAS  Google Scholar 

  106. Haritunians T, Mori A, O’Kelly J, Luong QT, Giles FJ, Koeffler HP (2007) Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia 21:333–339

    Article  PubMed  CAS  Google Scholar 

  107. Guix M, Faber AC, Wang SE et al (2008) Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest 118:2609–2619

    PubMed  CAS  Google Scholar 

  108. Jin Q, Esteva FJ (2008) Cross-Talk Between the ErbB/HER Family and the Type I Insulin-Like Growth Factor Receptor Signaling Pathway in Breast Cancer. J Mammary Gland Biol Neoplasia 13:485–498

    Article  PubMed  Google Scholar 

  109. Buck E, Eyzaguirre A, Brown E et al (2006) Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol Cancer Ther 5:2676–2684

    Article  PubMed  CAS  Google Scholar 

  110. Eichhorn PJ, Gili M, Scaltriti M et al (2008) Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 68:9221–9230

    Article  PubMed  CAS  Google Scholar 

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  1. The Research Institute, Center for Childhood Cancer, Nationwide Children’s Hospital, Columbus, OH, 43205, USA

    Peter J. Houghton

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  1. Dept. Family Medicine, University of Minnesota, Minneapolis, 55455, USA

    Vitaly A. Polunovsky

  2. Director, Center for Childhood Cancer, Nationwide Children’s Hospital, The Research Institute, 700 Children’s Drive 332, Columbus, 43205, USA

    Peter J. Houghton

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Houghton, P.J. (2009). mTOR and Cancer Therapy: General Principles. In: Polunovsky, V., Houghton, P. (eds) mTOR Pathway and mTOR Inhibitors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-271-1_6

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