Mammalian Target of Rapamycin: Discovery of Rapamycin Reveals a Signaling Pathway Important for Normal and Cancer Cell Growth

Seminars in Oncology

Volumn 36, Issue SUPPL. 3, 2009, Pages

  Gibbons, James J ^a   Abraham, Robert T ^a   Yu, Ker ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CISPLATIN; DEFOROLIMUS; DOXORUBICIN; EVEROLIMUS; FLUOROURACIL; GEMCITABINE; INITIATION FACTOR 4E BINDING PROTEIN 1; K RAS PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; PROTEIN P110; PROTEIN P85; PROTEIN TYROSINE KINASE; RAPAMYCIN; TEMSIROLIMUS;

ANGIOGENESIS; ARTICLE; BREAST CANCER; CANCER GROWTH; CANCER INHIBITION; CANCER THERAPY; CELL CYCLE PROGRESSION; CELL PROLIFERATION; CELL SURVIVAL; CLINICAL TRIAL; DRUG DOSE COMPARISON; DRUG DOSE REGIMEN; DRUG HALF LIFE; DRUG MECHANISM; DRUG MEGADOSE; ENDOMETRIUM CANCER; GENE EXPRESSION; GENE MUTATION; GLIOBLASTOMA; HEAD AND NECK CANCER; HUMAN; KIDNEY CANCER; MANTLE CELL LYMPHOMA; MEDULLOBLASTOMA; NONHUMAN; ONCOGENE C MYC; PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN SYNTHESIS;

ANIMALS; ANTIBIOTICS, ANTINEOPLASTIC; CELL PROLIFERATION; DRUG DISCOVERY; HUMANS; MODELS, BIOLOGICAL; NEOPLASMS; PROTEIN BIOSYNTHESIS; PROTEIN KINASES; SIGNAL TRANSDUCTION; SIROLIMUS;

EID: 72049117072     PISSN: 00937754     EISSN: None     Source Type: Journal    
DOI: 10.1053/j.seminoncol.2009.10.011     Document Type: Article

References (171)

1. Vezina C., Kudelski A., and Sehgal S.N. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 28 (1975) 721-726
2. Martel R.R., Klicius J., and Galet S. Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can J Physiol Pharmacol 55 (1977) 48-51
3. Dumont F.J., Staruch M.J., Koprak S.L., Melino M.R., and Sigal N.H. Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin. J Immunol 144 (1990) 251-258
4. Bierer B.E., Mattila P.S., Standaert R.F., et al. Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. Proc Natl Acad Sci U S A 87 (1990) 9231-9235
5. Heitman J., Movva N.R., and Hall M.N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253 (1991) 905-909
6. Brown E.J., Albers M.W., Shin T.B., et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369 (1994) 756-758
7. Sabatini D.M., Erdjument-Bromage H., Lui M., Tempst P., and Snyder S.H. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78 (1994) 35-43
8. Chiu M.I., Katz H., and Berlin V. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci U S A 91 (1994) 12574-12578
9. Sabers C.J., Martin M.M., Brunn G.J., et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 270 (1995) 815-822
10. Choi J., Chen J., Schreiber S.L., and Clardy J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 273 (1996) 239-242
11. Terada N., Lucas J.J., Szepesi A., Franklin R.A., Domenico J., and Gelfand E.W. Rapamycin blocks cell cycle progression of activated T cells prior to events characteristic of the middle to late G1 phase of the cycle. J Cell Physiol 154 (1993) 7-15
12. Morice W.G., Brunn G.J., Wiederrecht G., Siekierka J.J., and Abraham R.T. Rapamycin-induced inhibition of p34cdc2 kinase activation is associated with G1/S-phase growth arrest in T lymphocytes. J Biol Chem 268 (1993) 3734-3738
13. Morice W.G., Wiederrecht G., Brunn G.J., Siekierka J.J., and Abraham R.T. Rapamycin inhibition of interleukin-2-dependent p33cdk2 and p34cdc2 kinase activation in T lymphocytes. J Biol Chem 268 (1993) 22737-22745
14. Kuo C.J., Chung J., Fiorentino D.F., Flanagan W.M., Blenis J., and Crabtree G.R. Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature 358 (1992) 70-73
15. Barbet N.C., Schneider U., Helliwell S.B., Stansfield I., Tuite M.F., and Hall M.N. TOR controls translation initiation and early G1 progression in yeast. Mol Biol Cell 7 (1996) 25-42
16. Beretta L., Gingras A.C., Svitkin Y.V., Hall M.N., and Sonenberg N. Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EMBO J 15 (1996) 658-664
17. Brunn G.J., Hudson C.C., Sekulic A., et al. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277 (1997) 99-101
18. Gingras A.C., Raught B., and Sonenberg N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68 (1999) 913-963
19. Dorrello N.V., Peschiaroli A., Guardavaccaro D., Colburn N.H., Sherman N.E., and Pagano M. S6K1- and βTRCP-mediated degradation of PDC promotes protein translation and cell growth. Science 314 (2006) 467-471
20. Proud C.G., and Denton R.M. Molecular mechanisms for the control of translation by insulin. Biochem J 328 Part 2 (1997) 329-341
21. Wullschleger S., Loewith R., and Hall M.N. TOR signaling in growth and metabolism. Cell 124 (2006) 471-484
22. Browne G.J., and Proud C.G. A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin. Mol Cell Biol 24 (2004) 2986-2997
23. Proud C.G. mTORC1 signalling and mRNA translation. Biochem Soc Trans 37 (2009) 227-231
24. Ma X.M., and Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10 (2009) 307-318
25. Schmelzle T., and Hall M.N. TOR, a central controller of cell growth. Cell 103 (2000) 253-262
26. Yuan T.L., and Cantley L.C. PI3K pathway alterations in cancer: variations on a theme. Oncogene 27 (2008) 5497-5510
27. Sehgal S.N. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc 35 (2003) 7S-14S
28. Sehgal S.N., Camardo J.S., Scarola J.A., and Maida B.T. Rapamycin (sirolimus, rapamune). Curr Opin Nephrol Hypertens 4 (1995) 482-487
29. Lai J.H., and Tan T.H. CD28 signaling causes a sustained down-regulation of I kappa B alpha which can be prevented by the immunosuppressant rapamycin. J Biol Chem 269 (1994) 30077-30080
30. Ghosh P., Buchholz M.A., Yano S., Taub D., and Longo D.L. Effect of rapamycin on the cyclosporin A-resistant CD28-mediated costimulatory pathway. Blood 99 (2002) 4517-4524
31. Dufner A., and Thomas G. Ribosomal S6 kinase signaling and the control of translation. Exp Cell Res 253 (1999) 100-109
32. Kim D.H., and Sabatini D.M. Raptor and mTOR: subunits of a nutrient-sensitive complex. Curr Top Microbiol Immunol 279 (2004) 259-270
33. Fingar D.C., and Blenis J. Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 23 (2004) 3151-3171
34. Kimball S.R. Interaction between the AMP-activated protein kinase and mTOR signaling pathways. Med Sci Sports Exerc 38 (2006) 1958-1964
35. Hudson C.C., Liu M., Chiang G.G., et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22 (2002) 7004-7014
36. Zhong H., Chiles K., Feldser D., et al. Modulation of hypoxia-inducible factor 1-alpha 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 (2000) 1541-1545
37. Rachdi L., Balcazar N., Osorio-Duque F., et al. Disruption of Tsc2 in pancreatic beta cells induces beta cell mass expansion and improved glucose tolerance in a TORC1-dependent manner. Proc Natl Acad Sci U S A 105 (2008) 9250-9255
38. Anthony J.C., Anthony T.G., Kimball S.R., and Jefferson L.S. Signaling pathways involved in translational control of protein synthesis in skeletal muscle by leucine. J Nutr 131 (2001) 856S-860S
39. Peng T., Golub T.R., and Sabatini D.M. The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol Cell Biol 22 (2002) 5575-5584
40. Morrisett J.D., bdel-Fattah G., Hoogeveen R., et al. Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J Lipid Res 43 (2002) 1170-1180
41. Hoogeveen R.C., Ballantyne C.M., Pownall H.J., et al. Effect of sirolimus on the metabolism of apo. Transplantation 72 (2001) 1244-1250
42. Kim J.E., and Chen J. Regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes 53 (2004) 2748-2756
43. Huffman T.A., Mothe-Satney I., and Lawrence Jr. J.C. Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin. Proc Natl Acad Sci U S A 99 (2002) 1047-1052
44. Reue K., and Zhang P. The lipin protein family: dual roles in lipid biosynthesis and gene expression. FEBS Lett 582 (2008) 90-96
45. Ravikumar B., Vacher C., Berger Z., et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36 (2004) 585-595
46. Mizushima N., Levine B., Cuervo A.M., and Klionsky D.J. Autophagy fights disease through cellular self-digestion. Nature 451 (2008) 1069-1075
47. Jin S., DiPaola R.S., Mathew R., and White E. Metabolic catastrophe as a means to cancer cell death. J Cell Sci 120 (2007) 379-383
48. Abraham R.T. PI 3-kinase related kinases: 'big' players in stress-induced signaling pathways. DNA Repair (Amst) 3 (2004) 883-887
49. Andrade M.A., and Bork P. HEAT repeats in the Huntington's disease protein. Nat Genet 11 (1995) 115-116
50. Kim D.H., Sarbassov D.D., Ali S.M., et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110 (2002) 163-175
51. Hara K., Maruki Y., Long X., et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110 (2002) 177-189
52. Manning B.D., and Cantley L.C. United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Biochem Soc Trans 31 (2003) 573-578
53. Goncharova E.A., Goncharov D.A., Eszterhas A., et al. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem 277 (2002) 30958-30967
54. Inoki K., Li Y., Zhu T., Wu J., and Guan K.L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4 (2002) 648-657
55. Manning B.D., Tee A.R., Logsdon M.N., Blenis J., and Cantley L.C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 10 (2002) 151-162
56. Potter C.J., Pedraza L.G., and Xu T. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 4 (2002) 658-665
57. Li Y., Corradetti M.N., Inoki K., and Guan K.L. TSC2: filling the GAP in the mTOR signaling pathway. Trends Biochem Sci 29 (2004) 32-38
58. Long X., Lin Y., Ortiz-Vega S., Yonezawa K., and Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol 15 (2005) 702-713
59. Vander H.E., Lee S.I., Bandhakavi S., Griffin T.J., and Kim D.H. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 9 (2007) 316-323
60. Wang L., Harris T.E., Roth R.A., and Lawrence Jr. J.C. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 282 (2007) 20036-20044
61. Oshiro N., Takahashi R., Yoshino K., et al. The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. J Biol Chem 282 (2007) 20329-20339
62. Thedieck K., Polak P., Kim M.L., et al. PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS One 2 (2007) e1217
63. Faivre S., Kroemer G., and Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5 (2006) 671-688
64. Hara K., Yonezawa K., Weng Q.P., Kozlowski M.T., Belham C., and Avruch J. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem 273 (1998) 14484-14494
65. Kim E., Goraksha-Hicks P., Li L., Neufeld T.P., and Guan K.L. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 10 (2008) 935-945
66. Sancak Y., and Sabatini D.M. Rag proteins regulate amino-acid-induced mTORC1 signalling. Biochem Soc Trans 37 (2009) 289-290
67. Hardie D.G. Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 144 (2003) 5179-5183
68. Kimura N., Tokunaga C., Dalal S., et al. A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway. Genes Cells 8 (2003) 65-79
69. Inoki K., Zhu T., and Guan K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115 (2003) 577-590
70. Gwinn D.M., Shackelford D.B., Egan D.F., et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30 (2008) 214-226
71. Brugarolas J., Lei K., Hurley R.L., et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18 (2004) 2893-2904
72. Huang J., and Manning B.D. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 412 (2008) 179-190
73. Nourse J., Firpo E., Flanagan W.M., et al. Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. Nature 372 (1994) 570-573
74. Hashemolhosseini S., Nagamine Y., Morley S.J., Desrivieres S., Mercep L., and Ferrari S. Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J Biol Chem 273 (1998) 14424-14429
75. Muise-Helmericks R.C., Grimes H.L., Bellacosa A., Malstrom S.E., Tsichlis P.N., and Rosen N. Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem 273 (1998) 29864-29872
76. Di Como C.J., and Arndt K.T. Nutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases. Genes Dev 10 (1996) 1904-1916
77. Sarbassov D.D., Ali S.M., Kim D.H., et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14 (2004) 1296-1302
78. Sarbassov D.D., Guertin D.A., Ali S.M., and Sabatini D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307 (2005) 1098-1101
79. Huang J., Dibble C.C., Matsuzaki M., and Manning B.D. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 28 (2008) 4104-4115
80. Sarbassov D.D., Ali S.M., Sengupta S., et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22 (2006) 159-168
81. Ozes O.N., Akca H., Mayo L.D., et al. A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proc Natl Acad Sci U S A 98 (2001) 4640-4645
82. Tremblay F., Brule S., Hee U.S., et al. 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 (2007) 14056-14061
83. Tremblay F., Krebs M., Dombrowski L., et al. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 54 (2005) 2674-2684
84. O'Reilly K.E., Rojo F., She Q.B., et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66 (2006) 1500-1508
85. Guertin D.A., Stevens D.M., Saitoh M., et al. mTOR complex 2 is required for the development of prostate cancer induced by PTEN loss in mice. Cancer Cell 15 (2009) 148-159
86. Nardella C., Carracedo A., Alimonti A., et al. Differential requirement of mTOR in postmitotic tissues and tumorigenesis. Sci Signal 2 (2009) ra2
87. Dang C.V., O'Donnell K.A., Zeller K.I., Nguyen T., Osthus R.C., and Li F. The c-myc target gene network. Semin Cancer Biol 16 (2006) 253-264
88. Knies-Bamforth U.E., Fox S.B., Poulsom R., Evan G.I., and Harris A.L. c-Myc interacts with hypoxia to induce angiogenesis in vivo by a vascular endothelial growth factor-dependent mechanism. Cancer Res 64 (2004) 6563-6570
89. Kondo K., Kim W.Y., Lechpammer M., and Kaelin Jr. W.G. Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 1 (2003) E83
90. Patel S.A., and Simon M.C. Biology of hypoxia-inducible factor-2alpha in development and disease. Cell Death Differ 15 (2008) 628-634
91. Hait W.N., and Hambley T.W. Targeted cancer therapeutics. Cancer Res 69 (2009) 1263-1267
92. Inoki K., Corradetti M.N., and Guan K.L. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 37 (2005) 19-24
93. Johannessen C.M., Reczek E.E., James M.F., Brems H., Legius E., and Cichowski K. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci U S A 102 (2005) 8573-8578
94. Makowski L., and Hayes D.N. Role of LKB1 in lung cancer development. Br J Cancer 99 (2008) 683-688
95. Keniry M., and Parsons R. The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene 27 (2008) 5477-5485
96. Li J., Yen C., Liaw D., et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275 (1997) 1943-1947
97. Steck P.A., Pershouse M.A., Jasser S.A., et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15 (1997) 356-362
98. Li D.M., and Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res 57 (1997) 2124-2129
99. Podsypanina K., Ellenson L.H., Nemes A., et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A 96 (1999) 1563-1568
100. Neshat M.S., Mellinghoff I.K., Tran C., et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 98 (2001) 10314-10319
101. Podsypanina K., Lee R.T., 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 98 (2001) 10320-10325
102. 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 8 (2001) 249-258
103. Chang S.M., Wen P., Cloughesy T., et al. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23 (2005) 357-361
104. Galanis E., Buckner J.C., Maurer M.J., et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group study. J Clin Oncol 23 (2005) 5294-5304
105. Data on file (2006), Wyeth Pharmaceuticals, Inc, Philadelphia, PA
106. Lasithiotakis K.G., Sinnberg T.W., Schittek B., et al. Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells. J Invest Dermatol 128 (2008) 2013-2023
107. Paternot S., and Roger P.P. Combined inhibition of MEK and mammalian target of rapamycin abolishes phosphorylation of cyclin-dependent kinase 4 in glioblastoma cell lines and prevents their proliferation. Cancer Res 69 (2009) 4577-4581
108. Bertrand F.E., Spengemen J.D., Shelton J.G., and McCubrey J.A. Inhibition of PI3K, mTOR and MEK signaling pathways promotes rapid apoptosis in B-lineage ALL in the presence of stromal cell support. Leukemia 19 (2005) 98-102
109. Yu K., Toral-Barza L., Shi C., Zhang W.G., and Zask A. Response and determinants of cancer cell susceptibility to PI3K inhibitors: combined targeting of PI3K and Mek1 as an effective anticancer strategy. Cancer Biol Ther 7 (2008) 307-315
110. Kinkade C.W., Castillo-Martin M., Puzio-Kuter A., et al. Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 118 (2008) 3051-3064
111. Oza A.M., 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-NCIC IND 160 [abstract 3003]. J Clin Oncol 2006 Annual Proceedings Part I 24 Suppl 18s (2006) 121s
112. Tashiro H., Blazes M.S., Wu R., et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res 57 (1997) 3935-3940
113. Ollikainen M., Gylling A., Puputti M., et al. Patterns of PIK3CA alterations in familial colorectal and endometrial carcinoma. Int J Cancer 121 (2007) 915-920
114. Weinstein I.B., and Joe A.K. Mechanisms of disease: Oncogene addiction-a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 3 (2006) 448-457
115. Maxwell G.L., Risinger J.I., Gumbs C., et al. Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias. Cancer Res 58 (1998) 2500-2503
116. Steck P.A., Lin H., Langford L.A., et al. Functional and molecular analyses of 10q deletions in human gliomas. Genes Chromosomes Cancer 24 (1999) 135-143
117. Tsao H., Mihm Jr. M.C., and Sheehan C. PTEN expression in normal skin, acquired melanocytic nevi, and cutaneous melanoma. J Am Acad Dermatol 49 (2003) 865-872
118. Sehgal S.N. Immunosuppressive profile of rapamycin. Ann N Y Acad Sci 696 (1992) 1-8
119. Eng C.P., Sehgal S.N., and Vezina C. Activity of rapamycin (AY-22,989) against transplanted tumors. J Antibiot (Tokyo) 37 (1984) 1231-1237
120. Dilling M.B., Dias P., Shapiro D.N., Germain G.S., Johnson R.K., and Houghton P.J. Rapamycin selectively inhibits the growth of childhood rhabdomyosarcoma cells through inhibition of signaling via the type I insulin-like growth factor receptor. Cancer Res 54 (1994) 903-907
121. Garber K. Rapamycin's resurrection: a new way to target the cancer cell cycle. J Natl Cancer Inst 93 (2001) 1517-1519
122. Dancey J., and Sausville E.A. Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2 (2003) 296-313
123. Gibbons J.J., Discafani C., Peterson R., Hernandez R., Skotnicki J., and Frost P. The effect of CCI-779, a novel macrolide anti-tumor agent, on the growth of human tumor cells in vitro and in nude mouse xenografts in vivo [abstract 2000]. Proc Am Assoc Cancer Res 40 (1999) 301
124. Skotnicki J.S., Leone C.L., Smith A.L., et al. Design, synthesis and biological evaluation of C-42 hydroxyesters of rapamycin: the identification of CCI-779 [abstract 477]. Clin Cancer Res 7 (2001) 3749S-3750S
125. Shor B., Zhang W.G., Toral-Barza L., et al. A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis. Cancer Res 68 (2008) 2934-2943
126. Kuhn J.G., Chang S.M., Wen P.Y., et al. Pharmacokinetic and tumor distribution characteristics of temsirolimus in patients with recurrent malignant glioma. Clin Cancer Res 13 (2007) 7401-7406
127. Atkins M.B., Hidalgo M., Stadler W.M., 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 22 (2004) 909-918
128. Hosoi H., Dilling M.B., Shikata T., et al. Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells. Cancer Res 59 (1999) 886-894
129. Motzer R.J., Escudier B., Oudard S., et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372 (2008) 449-456
130. Dancey J.E. Inhibitors of the mammalian target of rapamycin. Expert Opin Invest Drugs 14 (2005) 313-328
131. Thomas G.V., Tran C., Mellinghoff I.K., et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 12 (2006) 122-127
132. Hu X., Pandolfi P.P., Li Y., Koutcher J.A., Rosenblum M., and Holland E.C. mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma. Neoplasia 7 (2005) 356-368
133. Geoerger B., Kerr K., Tang C.B., et al. 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 (2001) 1527-1532
134. Nathan C.A., Amirghahari N., Rong X., et al. Mammalian target of rapamycin inhibitors as possible adjuvant therapy for microscopic residual disease in head and neck squamous cell cancer. Cancer Res 67 (2007) 2160-2168
135. Teachey D.T., Obzut D.A., Cooperman J., et al. The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Blood 107 (2006) 1149-1155
136. Frost P., Moatamed F., Hoang B., et al. In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model. Blood 104 (2004) 4181-4187
137. Zeng Z., Sarbassov D.D., Samudio I.J., et al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109 (2007) 3509-3512
138. Gera J.F., Mellinghoff I.K., Shi Y., et al. AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin D1 and c-myc expression. J Biol Chem 279 (2004) 2737-2746
139. Johnsen J.I., Segerstrom L., Orrego A., et al. Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo. Oncogene 27 (2008) 2910-2922
140. Del Bufalo D., Ciuffreda L., Trisciuoglio D., et al. Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 66 (2006) 5549-5554
141. Bohm A., Aichberger K.J., Mayerhofer M., et al. Targeting of mTOR is associated with decreased growth and decreased VEGF expression in acute myeloid leukaemia cells. Eur J Clin Invest 39 (2009) 395-405
142. Costa L.F., Balcells M., Edelman E.R., Nadler L.M., and Cardoso A.A. Proangiogenic stimulation of bone marrow endothelium engages mTOR and is inhibited by simultaneous blockade of mTOR and NF-kappaB. Blood 107 (2006) 285-292
143. Amornphimoltham P., Patel V., Leelahavanichkul K., Abraham R.T., and Gutkind J.S. A retroinhibition approach reveals a tumor cell-autonomous response to rapamycin in head and neck cancer. Cancer Res 68 (2008) 1144-1153
144. Wislez M., Spencer M.L., Izzo J.G., et al. Inhibition of mammalian target of rapamycin reverses alveolar epithelial neoplasia induced by oncogenic K-ras. Cancer Res 65 (2005) 3226-3235
145. Wangpaichitr M., Wu C., You M., et al. Inhibition of mTOR restores cisplatin sensitivity through down-regulation of growth and anti-apoptotic proteins. Eur J Pharmacol 591 (2008) 124-127
146. Grunwald V., DeGraffenried L., Russel D., Friedrichs W.E., Ray R.B., and Hidalgo M. Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells. Cancer Res 62 (2002) 6141-6145
147. deGraffenried L.A., Friedrichs W.E., Russell D.H., et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res 10 (2004) 8059-8067
148. Punt C.J., Boni J., Bruntsch U., Peters M., and Thielert C. Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors. Ann Oncol 14 (2003) 931-937
149. Hudes G., Carducci M., Tomczak P., et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356 (2007) 2271-2281
150. Kaelin W.G. Von Hippel-Lindau disease. Annu Rev Pathol 2 (2007) 145-173
151. Semenza G.L. Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol 19 (2009) 12-16
152. Dutcher J.P., de S.P., McDermott C., et al. Effect of temsirolimus versus interferon-alpha on outcome of patients with advanced renal cell carcinoma of different tumor histologies. Med Oncol 26 (2009) 202-209
153. Fischer J., Palmedo G., von K.R., et al. Duplication and overexpression of the mutant allele of the MET proto-oncogene in multiple hereditary papillary renal cell tumours. Oncogene 17 (1998) 733-739
154. Faletto D.L., Kaplan D.R., Halverson D.O., Rosen E.M., and Vande Woude G.F. Signal transduction in c-met mediated motogenesis. EXS 65 (1993) 107-130
155. Bratslavsky G., Sudarshan S., Neckers L., and Linehan W.M. Pseudohypoxic pathways in renal cell carcinoma. Clin Cancer Res 13 (2007) 4667-4671
156. Hess G., Romaguera J., Verhoef G., et al. Phase 3 study of patients with relapsed, refractory mantle cell lymphoma treated with temsirolimus compared with investigator's choice therapy [abstract 8513]. J Clin Oncol, 2008 ASCO Annual Meeting Proceedings 26 Suppl 15 (2008) 457s
157. Smith M.R. Mantle cell lymphoma: advances in biology and therapy. Curr Opin Hematol 15 (2008) 415-421
158. Dal Col J., Zancai P., Terrin L., et al. Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood 111 (2008) 5142-5151
159. Hipp S., Ringshausen I., Oelsner M., Bogner C., Peschel C., and Decker T. Inhibition of the mammalian target of rapamycin and the induction of cell cycle arrest in mantle cell lymphoma cells. Haematologica 90 (2005) 1433-1434
160. Yazbeck V.Y., Buglio D., Georgakis G.V., et al. Temsirolimus downregulates p21 without altering cyclin D1 expression and induces autophagy and synergizes with vorinostat in mantle cell lymphoma. Exp Hematol 36 (2008) 443-450
161. Wu L., Birle D.C., and Tannock I.F. 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 (2005) 2825-2831
162. Leone M., Crowell K.J., Chen J., et al. The FRB domain of mTOR: NMR solution structure and inhibitor design. Biochemistry (Mosc) 45 (2006) 10294-10302
163. Edinger A.L., Linardic C.M., Chiang G.G., Thompson C.B., and Abraham R.T. Differential effects of rapamycin on mammalian target of rapamycin signaling functions in mammalian cells. Cancer Res 63 (2003) 8451-8460
164. Thoreen C.C., Kang S.A., Chang J.W., et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284 (2009) 8023-8032
165. Yu K., Toral-Barza L., Shi C., et al. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 69 (2009) 6232-6240
166. Cloughesy T.F., Yoshimoto K., Nghiemphu P., et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 5 (2008) e8
167. Feldman M.E., Apsel B., Uotila A., et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7 (2009) e38
168. Garcia-Martinez J.M., Moran J., Clarke R.G., et al. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J 421 (2009) 29-42
169. Guertin D.A., Stevens D.M., Thoreen C.C., et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11 (2006) 859-871
170. Maira S.M., Stauffer F., Brueggen J., et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 7 (2008) 1851-1863
171. Sonenberg N., and Hinnebusch A.G. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136 (2009) 731-745