Combinations of Cytotoxic Drugs, Ionizing Radiation, and Mammalian Target of Rapamycin (mTOR) Inhibitors

  • Jann N. Sarkaria
Part of the Medical Radiology book series (MEDRAD)

9.7 Conclusion

Rapamycin and its analogs are versatile drugs with proven efficacy in cardiovascular and transplant medicine and with promising results in early cancer clinical trials. In specific tumor types, a select minority of patients likely will benefit from monotherapy. The challenge for the future will be to dissect further the molecular signaling pathways modulated by rapamycin in order to appreciate fully the molecular mechanisms underpinning sensitivity or resistance to mTOR inhibition. This understanding will provide insight into rational combinations of mTOR inhibitors with classic cytotoxic agents, radiation, and other molecularly targeted therapies.


Vascular Endothelial Growth Factor Mantle Cell Lymphoma mTOR Inhibitor Mammalian Target mTOR Signaling 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abraham RT (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Devel 15:2177–2196PubMedCrossRefGoogle Scholar
  2. Abraham RT (2004) mTOR as a positive regulator of tumor cell responses to hypoxia. Curr Topics Microbiol Immunol 279:299–319Google Scholar
  3. Atkins MB, Hidalgo M, Stadler WM et al (2004) 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 22:909–918PubMedCrossRefGoogle Scholar
  4. Benedetti A de, Harris AL (1999) eIF4E expression in tumors: its possible role in progression of malignancies. Int J Biochem Cell Biol 31:59–72PubMedCrossRefGoogle Scholar
  5. Bentzen SM (2003) Repopulation in radiation oncology: perspectives of clinical research. Int J Radiat Biol 79:581–585PubMedCrossRefGoogle Scholar
  6. Bertrand FE, Spengemen JD, Shelton JG et al (2005) Inhibition of PI3K, mTOR and MEK signaling pathways promotes rapid apoptosis in B-lineage ALL in the presence of stromal cell support. Leukemia 19:98–102PubMedGoogle Scholar
  7. 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 120:747–759PubMedCrossRefGoogle Scholar
  8. Boulay A, Rudloff J, Ye J et al (2005) Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res 11:5319–5328PubMedCrossRefGoogle Scholar
  9. Brown EJ, Albers MW, Shin TB et al (1994) A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369:756–758PubMedCrossRefGoogle Scholar
  10. Brunn GJ, Hudson CC, Sekulic A et al (1997) Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277:99–101PubMedCrossRefGoogle Scholar
  11. Burchert A, Wang Y, Cai D et al (2005) Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia 19:1774–1782PubMedCrossRefGoogle Scholar
  12. Castro AF, Rebhun JF, Clark GJ et al (2003) Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin-and farnesylation-dependent manner. J Biol Chem 278:32493–32496PubMedCrossRefGoogle Scholar
  13. Chang SM, Wen P, Cloughesy T et al (2005) Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23:357–361PubMedCrossRefGoogle Scholar
  14. Corradetti MN, Inoki K, Bardeesy N et al (2004) Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 18:1533–1538PubMedCrossRefGoogle Scholar
  15. Cutler NS, Heitman J, Cardenas ME (1999) TOR kinase homologs function in a signal transduction pathway that is conserved from yeast to mammals. Mol Cell Endocrinol 155:135–142PubMedCrossRefGoogle Scholar
  16. Dan HC, Sun M, Yang L et al (2002) Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J Biol Chem 277:35364–35370PubMedCrossRefGoogle Scholar
  17. De Graffenried LA, Friedrichs WE, Russell DH et al (2004) Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt activity. Clin Cancer Res 10:8059–8067CrossRefGoogle Scholar
  18. Dengler J, Bubnoff N von, Decker T et al (2005) Combination of imatinib with rapamycin or RAD001 acts synergistically only in Bcr-Abl-positive cells with moderate resistance to imatinib. Leukemia 19:1835–1838PubMedCrossRefGoogle Scholar
  19. Dudkin L, Dilling MB, Cheshire PJ et al (2001) Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 7:1758–1764PubMedGoogle Scholar
  20. Durocher D, Jackson SP (2001) DNA-PK, ATM and ATR as sensors of DNA damage: Variations on a theme? Curr Opinion Cell Biol 13:225–231PubMedCrossRefGoogle Scholar
  21. Edinger AL, Linardic CM, Chiang GG et al (2003) Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. Cancer Res 63:8451–8460PubMedGoogle Scholar
  22. Eng CP, Sehgal SN, Vezina C (1984) Activity of rapamycin (AY-22,989) against transplanted tumors. J Antibiot (Tokyo) 37:1231–1237PubMedGoogle Scholar
  23. Eshleman JS, Carlson BL, Mladek AC et al (2002) Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res 62:7291–7297PubMedGoogle Scholar
  24. Fowler JF (2001) Biological factors influencing optimum fractionation in radiation therapy. Acta Oncol 40:712–717PubMedCrossRefGoogle Scholar
  25. Galanis E, Buckner JC, Maurer MJ et al (2005) Phase II trial of Temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 23:5294–5304PubMedCrossRefGoogle Scholar
  26. 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 11:1457–1466PubMedCrossRefGoogle Scholar
  27. Gemmill RM, Zhou M, Costa L et al (2005) Synergistic growth inhibition by iressa and rapamycin is modulated by VHL mutations in renal cell carcinoma. Br J Cancer 92:2266–2277PubMedCrossRefGoogle Scholar
  28. Geoerger B, Kerr K, Tang CB et al (2001) Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res 61:1527–1532PubMedGoogle Scholar
  29. Ghosh PM, Malik SN, Bedolla RG et al (2005) Signal transduction pathways in androgen-dependent and-independent prostate cancer cell proliferation. Endocr Relat Cancer 12:119–134PubMedCrossRefGoogle Scholar
  30. Gingras AC, Kennedy SG, O’Leary MA et al (1998) 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Devel 12:502–513PubMedGoogle Scholar
  31. Gingras AC, Gygi SP, Raught B et al (1999) Regulation of 4EBP1 phosphorylation: a novel two-step mechanism. Genes Devel 13:1422–1437PubMedGoogle Scholar
  32. Goudar RK, Shi Q, Hjelmeland MD et al (2005) Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition. Mol Cancer Ther 4:101–112PubMedGoogle Scholar
  33. Grant S, Qiao L, Dent P (2002) Roles of ERBB family receptor tyrosine kinases, and downstream signaling pathways, in the control of cell growth and survival. Front Biosci 7:376–389Google Scholar
  34. Guba M, Breitenbuch P von, Steinbauer M et al (2002) Rapamycin inhibits primary and metastatic tumor growth by anti-angiogenesis: involvement of vascular endothelial growth factor. Nature Med 8:128–135PubMedCrossRefGoogle Scholar
  35. Hahn M, Li W, Yu C et al (2005) Rapamycin and UCN-01 synergistically induce apoptosis in human leukemia cells through a process that is regulated by the Raf-1/MEK/ERK, Akt, and JNK signal transduction pathways. Mol Cancer Ther 4:457–470PubMedGoogle Scholar
  36. Hara K, Maruki Y, Long X et al (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110:177–189PubMedCrossRefGoogle Scholar
  37. Harris AL (2002) Hypoxia: a key regulatory factor in tumour growth. Nature Rev Cancer 2:38–47CrossRefGoogle Scholar
  38. Herbert TP, Tee AR, Proud CG (2002) The extracellular signal-regulated kinase pathway regulates the phosphorylation of 4E-BP1 at multiple sites. J Biol Chem 277:11591–11596PubMedCrossRefGoogle Scholar
  39. Holland EC, Celestino J, Dai C et al (2000) Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nature Genet 25:55–57PubMedCrossRefGoogle Scholar
  40. Houchens DP, Ovejera AA, Riblet SM et al (1983). Human brain tumor xenografts in nude mice as a chemotherapy model. Eur J Cancer Clin Oncol 19:799–805PubMedCrossRefGoogle Scholar
  41. 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 22:7004–7014PubMedCrossRefGoogle Scholar
  42. Inoki K, Li Y, Zhu T et al (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biol 4:648–657PubMedCrossRefGoogle Scholar
  43. Inoki K, Li Y, Xu T et al (2003) Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17:1829–1834PubMedCrossRefGoogle Scholar
  44. Jaakkola P, Mole DR, Tian YM et al (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472PubMedGoogle Scholar
  45. Jefferies HB, Fumagalli S, Dennis PB et al (1997) Rapamycin suppresses 5’TOP mRNA translation through inhibition of p70s6k. EMBO J 16:3693–3704PubMedCrossRefGoogle Scholar
  46. Kim Do H, Sarbassov D, Ali SM et al (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110:163–175CrossRefGoogle Scholar
  47. Kirkegaard T, Witton CJ, McGlynn LM et al (2005) AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol 207:139–146PubMedCrossRefGoogle Scholar
  48. Kozak M (1991) An analysis of vertebrate mRNA sequences: intimations of translational control. J Cell Biol 115:887–903PubMedCrossRefGoogle Scholar
  49. Laughner E, Taghavi P, Chiles K et al (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 21:3995–4004PubMedCrossRefGoogle Scholar
  50. Luan FL, Ding R, Sharma VK et al (2003) Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int 63:917–926PubMedCrossRefGoogle Scholar
  51. Ly C, Arechiga AF, Melo JV et al (2003) Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res 63:5716–5722PubMedGoogle Scholar
  52. Majumder PK, Febbo PG, Bikoff R et al (2004) mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nature Med 10:594–601PubMedCrossRefGoogle Scholar
  53. Margolin K, Longmate J, Barattam T et al (2005) CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer 104:1045–1048PubMedCrossRefGoogle Scholar
  54. Mayerhofer M, Valent P, Sperr WR et al (2002) 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 100:3767–3775PubMedCrossRefGoogle Scholar
  55. Mazure NM, Chen EY, Laderoute KR et al (1997) Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood 90:3322–3331PubMedGoogle Scholar
  56. Mohi MG, Boulton C, Gu TL et al (2004) Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci USA 101:3130–3135PubMedCrossRefGoogle Scholar
  57. Mothe-Satney I, Brunn GJ, McMahon LP et al (2000) Mammalian target of rapamycin-dependent phosphorylation of PHAS-I in four (S/T)P sites detected by phospho-specific antibodies. J Biol Chem 275:33836–33843PubMedCrossRefGoogle Scholar
  58. Mousses S, Wagner U, Chen Y et al (2001) Failure of hormone therapy in prostate cancer involves systematic restoration of androgen responsive genes and activation of rapamycin sensitive signaling. Oncogene 20:6718–6723PubMedCrossRefGoogle Scholar
  59. Neshat MS, Mellinghoff IK, Tran C et al (2001) Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. PNAS 98:10314–10319PubMedCrossRefGoogle Scholar
  60. Potter CJ, Pedraza LG, Xu T (2002) Akt regulates growth by directly phosphorylating Tsc2. Nature Cell Biol 4:658–665PubMedCrossRefGoogle Scholar
  61. Rao RD, Buckner JC, Sarkaria JN (2004) Mammalian target of rapamycin (mTOR) inhibitors as anti-cancer agents. Curr Cancer Drug Targets 4:621–635PubMedCrossRefGoogle Scholar
  62. Rao RD, Mladek AC, Lamont JD et al (2005) Disruption of parallel and converging signaling pathways contribute to the synergistic anti-tumor effects of simultaneous mTOR and EGFR inhibition in GBM cells. Neoplasia 7, epubGoogle Scholar
  63. Raught B, Gingras AC, Sonenberg N (2001) The target of rapamycin (TOR) proteins. Proc Natl Acad Sci USA 98:7037–7044PubMedCrossRefGoogle Scholar
  64. Sabatini DM, Erdjument-Bromage H, Lui M et al (1994) RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78:35–43PubMedCrossRefGoogle Scholar
  65. Sarbassov DD, Guertin DA, Ali SM et al (2005) Phosphorylation and regulation of Akt/PKB by the Rictor-mTOR complex. Science 307:1098–1101PubMedCrossRefGoogle Scholar
  66. Saucedo LJ, Gao X, Chiarelli DA et al (2003) Rheb promotes cell growth as a component of the insulin/TOR signalling network. (Erratum in Nat Cell Biol 2003 5:680). Nature Cell Biol 5:566–571PubMedCrossRefGoogle Scholar
  67. Sekulic A, Hudson CC, Homme JL et al (2000) A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res 60:3504–3513PubMedGoogle Scholar
  68. Shaw RJ, Bardeesy N, Manning BD et al (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6:91–99PubMedCrossRefGoogle Scholar
  69. Shi Y, Frankel A, Radvanyi LG et al (1995) Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro. Cancer Res 55:1982–1988PubMedGoogle Scholar
  70. Shinohara ET, Cao C, Niermann K et al (2005) Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene 24:5414–5422PubMedCrossRefGoogle Scholar
  71. Sun SY, Rosenberg LM, Wang X et al (2005) Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 65:7052–7058PubMedCrossRefGoogle Scholar
  72. Takeuchi H, Kondo Y, Fujiwara K et al (2005) Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res 65:3336–3346PubMedGoogle Scholar
  73. Tee AR, Fingar DC, Manning BD et al (2002) 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 99:13571–13576PubMedCrossRefGoogle Scholar
  74. Vinals F, Chambard JC, Pouyssegur J (1999) p70 S6 kinase-mediated protein synthesis is a critical step for vascular endothelial cell proliferation. J Biol Chem 274:26776–26782PubMedCrossRefGoogle Scholar
  75. Volarevic S, Thomas G (2001) Role of S6 phosphorylation and S6 kinase in cell growth. Prog Nucleic Acid Res Molec Biol 65:101–127CrossRefGoogle Scholar
  76. Wan X, Helman LJ (2002) Effect of insulin-like growth factor II on protecting myoblast cells against cisplatin-induced apoptosis through p70 S6 kinase pathway. Neoplasia 4:400–408PubMedCrossRefGoogle Scholar
  77. Witzig TE, Geyer SM, Ghobrial I et al (2005) Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23:5347–5356PubMedCrossRefGoogle Scholar
  78. Wu L, Birle DC, Tannock IF (2005) Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells and xenografts. Cancer Res 65:2825–2831PubMedCrossRefGoogle Scholar
  79. Yu F, White SB, Zhao Q et al (2001) HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci USA 98:9630–9635PubMedCrossRefGoogle Scholar
  80. 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 60:1541–1545PubMedGoogle Scholar
  81. Zhou BB, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408:433–439PubMedCrossRefGoogle Scholar
  82. Zundel W, Schindler C, Haas-Kogan D et al (2000) Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Devel 14:391–396PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2006

Authors and Affiliations

  • Jann N. Sarkaria
    • 1
  1. 1.Department of OncologyRochesterUSA

Personalised recommendations