Mammalian target of rapamycin: A central node of complex signaling cascades

International Journal of Clinical and Experimental Pathology

Volumn 4, Issue 5, 2011, Pages 476-495

  Dobashi, Yoh ^a   Watanabe, Yasutaka ^a   Miwa, Chihiro ^a   Suzuki, Sakae ^a   Koyama, Shinichiro ^a  

^a JICHI MEDICAL UNIVERSITY   (Japan)

Author keywords

Lung cancer; Molecular targeting therapy; Mtor; Rapamycin

Indexed keywords

ANTINEOPLASTIC ANTIBIOTIC; MTORC1 COMPLEX, HUMAN; PROTEIN; RAPAMYCIN; TARGET OF RAPAMYCIN KINASE;

ANIMAL; CELL PROLIFERATION; DRUG EFFECT; HUMAN; METABOLISM; NEOPLASM; PATHOLOGY; PHOSPHORYLATION; PHYSIOLOGY; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; ANTIBIOTICS, ANTINEOPLASTIC; CELL PROLIFERATION; HUMANS; NEOPLASMS; PHOSPHORYLATION; PROTEINS; SIGNAL TRANSDUCTION; SIROLIMUS; TOR SERINE-THREONINE KINASES;

EID: 80055027842     PISSN: None     EISSN: 19362625     Source Type: Journal    
DOI: None     Document Type: Review

References (115)

1. Vignot S, Faivre S, Aguirre D and Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 2005; 16: 525-537.
2. Wullschleger S, Loewith R and Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124: 471-484.
3. Petroulakis E, Mamane Y, Le Bacquer O, Shahbazian D and Sonenberg N. mTOR signaling: implications for cancer and anticancer therapy. Br J Cancer 2006; 94: 195-199.
4. Fingar DC 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 2004; 23: 3151-3171.
5. Hay N and Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004; 18: 1926-1945.
6. Schmelzle T and Hall MN. TOR, a central controller of cell growth. Cell 2000; 103: 253-262.
7. Gingras AC, Raught B and Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev 2001; 15: 807-826.
8. Crespo JL and Hall MN. Elucidating TOR signaling and rapamycin action: lessons from Saccharomyces cerevisiae. Microbiol Mol Biol Rev 2002; 66: 579-591, table of contents.
9. Janus A, Robak T and Smolewski P. The mammalian target of the rapamycin (mTOR) kinase pathway: its role in tumourigenesis and targeted antitumour therapy. Cell Mol Biol Lett 2005; 10: 479-498.
10. Hynes NE and Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005; 5: 341-354.
11. Bjornsti MA and Houghton PJ. The TOR pathway: a target for cancer therapy. Nat Rev Cancer 2004; 4: 335-348.
12. Guertin DA and Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med 2005; 11: 353-361.
13. Kim JE and Chen J. Cytoplasmic-nuclear shuttling of FKBP12-rapamycin-associated protein is involved in rapamycin-sensitive signaling and translation initiation. Proc Natl Acad Sci U S A 2000; 97: 14340-14345.
14. Proud CG. mTOR-mediated regulation of translation factors by amino acids. Biochem BiophysRes Commun 2004; 313: 429-436.
15. Schalm SS, Fingar DC, Sabatini DM and Blenis J. TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol 2003; 13: 797-806.
16. Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P and Sabatini DM. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003; 11: 895-904.
17. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P and Sabatini DM. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14: 1296-1302.
18. Sarbassov DD, Ali SM and Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol 2005; 17: 596-603.
19. Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F, Kiyama H, Yonezawa K and Yamanaka S. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol 2004; 24: 6710-6718.
20. Jacinto E and Hall MN. Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 2003; 4: 117-126.
21. Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C and Blenis J. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 2004; 24: 200-216.
22. Takuwa N, Fukui Y and Takuwa Y. Cyclin D1 expression mediated by phosphatidylinositol 3-kinase through mTOR-p70(S6K)-independent signaling in growth factor-stimulated NIH 3T3 fibroblasts. Mol Cell Biol 1999; 19: 1346-1358.
23. Pene F, Claessens YE, Muller O, Viguie F, Mayeux P, Dreyfus F, Lacombe C and Bouscary D. Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene 2002; 21: 6587-6597.
24. Otulakowski G, Duan W and O'Brodovich H. Global and Gene-specific Translational Regulation in Rat Lung Development. Am J Respir Cell Mol Biol 2008;
25. Kim JE and Chen J. regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes 2004; 53: 2748-2756.
26. Phornphutkul C, Wu KY, Auyeung V, Chen Q and Gruppuso PA. mTOR signaling contributes to chondrocyte differentiation. Dev Dyn 2008;
27. Pouyssegur J, Dayan F and Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006; 441: 437-443.
28. Shaw RJ and Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006; 441: 424-430.
29. Lum JJ, DeBerardinis RJ and Thompson CB. Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol 2005; 6: 439-448.
30. Mamane Y, Petroulakis E, LeBacquer O and Sonenberg N. mTOR, translation initiation and cancer. Oncogene 2006; 25: 6416-6422.
31. Li B, Desai SA, MacCorkle-Chosnek RA, Fan L and Spencer DM. A novel conditional Akt 'survival switch' reversibly protects cells from apoptosis. Gene Ther 2002; 9: 233-244.
32. Vaira V, Lee CW, Goel HL, Bosari S, Languino LR and Altieri DC. Regulation of survivin expression by IGF-1/mTOR signaling. Oncogene 2007; 26: 2678-2684.
33. Hwang SK, Minai-Tehrani A, Lim HT, Shin JY, An GH, Lee KH, Park KR, Kim YS, Beck GR, Jr., Yang HS and Cho MH. Decreased level of PDCD4 (programmed cell death 4) protein activated cell proliferation in the lung of A/J mouse. J Aerosol Med Pulm Drug Deliv 2010; 23: 285-293.
34. Proud CG. The eukaryotic initiation factor 4Ebinding proteins and apoptosis. Cell Death Differ 2005; 12: 541-546.
35. Tsang CK, Liu H and Zheng XF. mTOR binds to the promoters of RNA polymerase I- and IIItranscribed genes. Cell Cycle 2010; 9: 953-957.
36. Kristof AS, Marks-Konczalik J, Billings E and Moss J. Stimulation of signal transducer and activator of transcription-1 (STAT1)-dependent gene transcription by lipopolysaccharide and interferon-gamma is regulated by mammalian target of rapamycin. J Biol Chem 2003; 278: 33637-33644.
37. Gingras AC, Raught B and Sonenberg N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 1999; 68: 913-963.
38. Armengol G, Rojo F, Castellvi J, Iglesias C, Cuatrecasas M, Pons B, Baselga J and Ramon y Cajal S. 4E-binding protein 1: a key molecular "funnel factor" in human cancer with clinical implications. Cancer Res 2007; 67: 7551-7555.
39. Wang X, Li W, Parra JL, Beugnet A and Proud CG. The C terminus of initiation factor 4Ebinding protein 1 contains multiple regulatory features that influence its function and phosphorylation. Mol Cell Biol 2003; 23: 1546-1557.
40. Wang X, Li W, Williams M, Terada N, Alessi DR and Proud CG. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J 2001; 20: 4370-4379.
41. Lee DF and Hung MC. All roads lead to mTOR: integrating inflammation and tumor angiogenesis. Cell Cycle 2007; 6: 3011-3014.
42. Wan X and Helman LJ. The biology behind mTOR inhibition in sarcoma. Oncologist 2007; 12: 1007-1018.
43. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296: 1655-1657.
44. Rhoads JM, Niu X, Odle J and Graves LM. Role of mTOR signaling in intestinal cell migration. Am J Physiol Gastrointest Liver Physiol 2006; 291: G510-517.
45. Inoki K, Zhu T and Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003; 115: 577-590.
46. Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P, Coadwell J and Hawkins PT. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 1998; 279: 710-714.
47. Toker A and Newton AC. Akt/protein kinase B is regulated by autophosphorylation at the hypothetical PDK-2 site. J Biol Chem 2000; 275: 8271-8274.
48. Sarbassov DD, Guertin DA, Ali SM and Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307: 1098-1101.
49. Luo J, Manning BD and Cantley LC. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 2003; 4: 257-262.
50. Ma L, Chen Z, Erdjument-Bromage H, Tempst P and Pandolfi PP. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005; 121: 179-193.
51. Arvisais EW, Romanelli A, Hou X and Davis JS. AKT-independent phosphorylation of TSC2 and activation of mTOR and ribosomal protein S6 kinase signaling by prostaglandin F2alpha. J Biol Chem 2006; 281: 26904-26913.
52. Inoki K, Corradetti MN and Guan KL. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 2005; 37: 19-24.
53. Long X, Lin Y, Ortiz-Vega S, Yonezawa K and Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol 2005; 15: 702-713.
54. Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 2005; 8: 179-183.
55. Foster KG and Fingar DC. Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony. J Biol Chem 2010; 285: 14071-14077.
56. Acosta-Jaquez HA, Keller JA, Foster KG, Ekim B, Soliman GA, Feener EP, Ballif BA and Fingar DC. Site-specific mTOR phosphorylation promotes mTORC1-mediated signaling and cell growth. Mol Cell Biol 2009; 29: 4308-4324.
57. Soliman GA, Acosta-Jaquez HA, Dunlop EA, Ekim B, Maj NE, Tee AR and Fingar DC. mTOR Ser-2481 autophosphorylation monitors mTORC-specific catalytic activity and clarifies rapamycin mechanism of action. J Biol Chem 285: 7866-7879.
58. Caron E, Ghosh S, Matsuoka Y, Ashton-Beaucage D, Therrien M, Lemieux S, Perreault C, Roux PP and Kitano H. A comprehensive map of the mTOR signaling network. Mol Syst Biol 2010; 6: 453.
59. Chiang GG and Abraham RT. Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. J Biol Chem 2005; 280: 25485-25490.
60. Holz MK and Blenis J. Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J Biol Chem 2005; 280: 26089-26093.
61. Astrinidis A, Cash TP, Hunter DS, Walker CL, Chernoff J and Henske EP. Tuberin, the tuberous sclerosis complex 2 tumor suppressor gene product, regulates Rho activation, cell adhesion and migration. Oncogene 2002; 21: 8470-8476.
62. Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA and Thomas G. Phosphorylation and activation of p70s6k by PDK1. Science 1998; 279: 707-710.
63. Manning BD. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 2004; 167: 399-403.
64. Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J and Thomas G. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004; 431: 200-205.
65. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J and Rosen N. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66: 1500-1508.
66. Young DA and Nickerson-Nutter CL. mTOR--beyond transplantation. Curr Opin Pharmacol 2005; 5: 418-423.
67. Gershlick AH. Drug eluting stents in 2005. Heart 2005; 91 Suppl 3: iii24-31.
68. Balsara BR, Pei J, Mitsuuchi Y, Page R, Klein-Szanto A, Wang H, Unger M and Testa JR. Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis 2004; 25: 2053-2059.
69. Feng Z, Fan X, Jiao Y and Ban K. Mammalian target of rapamycin regulates expression of beta-catenin in hepatocellular carcinoma. Hum Pathol 2011;
70. Molinolo AA, Hewitt SM, Amornphimoltham P, Keelawat S, Rangdaeng S, Meneses Garcia A, Raimondi AR, Jufe R, Itoiz M, Gao Y, Saranath D, Kaleebi GS, Yoo GH, Leak L, Myers EM, Shintani S, Wong D, Massey HD, Yeudall WA, Lonardo F, Ensley J and Gutkind JS. Dissecting the Akt/mammalian target of rapamycin signaling network: emerging results from the headand neck cancer tissue array initiative. Clin Cancer Res 2007; 13: 4964-4973.
71. Wong AS, Kim SO, Leung PC, Auersperg N and Pelech SL. Profiling of protein kinases in the neoplastic transformation of human ovarian surface epithelium. Gynecol Oncol 2001; 82: 305-311.
72. Couch FJ, Wang XY, Wu GJ, Qian J, Jenkins RB and James CD. Localization of PS6K to chromosomal region 17q23 and determination of its amplification in breast cancer. Cancer Res 1999; 59: 1408-1411.
73. Easton JB and Houghton PJ. mTOR and cancer therapy. Oncogene 2006; 25: 6436-6446.
74. Jones RM, Branda J, Johnston KA, Polymenis M, Gadd M, Rustgi A, Callanan L and Schmidt EV. An essential E box in the promoter of the gene encoding the mRNA cap-binding protein (eukaryotic initiation factor 4E) is a target for activation by c-myc. Mol Cell Biol 1996; 16: 4754-4764.
75. Vega F, Medeiros LJ, Leventaki V, Atwell C, Cho-Vega JH, Tian L, Claret FX and Rassidakis GZ. Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Cancer Res 2006; 66: 6589-6597.
76. Jiang H, Coleman J, Miskimins R and Miskimins WK. Expression of constitutively active 4EBP-1 enhances p27Kip1 expression and inhibits proliferation of MCF7 breast cancer cells. Cancer Cell Int 2003; 3: 2.
77. Rowinsky EK. Targeting the molecular target of rapamycin (mTOR). Curr Opin Oncol 2004; 16: 564-575.
78. Pantuck AJ, Seligson DB, Klatte T, Yu H, Leppert JT, Moore L, O'Toole T, Gibbons J, Belldegrun AS and Figlin RA. Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy. Cancer 2007; 109: 2257-2267.
79. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D and Oberg K. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 514-523.
80. Dobashi Y, Suzuki S, Sato E, Hamada Y, Yanagawa T and Ooi A. EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors. Mod Pathol 2009; 22: 1328-1340.
81. Fingar DC, Salama S, Tsou C, Harlow E and Blenis J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev 2002; 16: 1472-1487.
82. Dobashi Y, Suzuki S, Matsubara H, Kimura M, Endo S and Ooi A. Critical and diverse involvement of Akt/mammalian target of rapamycin signaling in human lung carcinomas. Cancer 2009; 115: 107-118.
83. Dobashi Y, Suzuki S, Kimura M, Matsubara H, Tsubochi H, Imoto I and Ooi A. Paradigm of kinase-driven pathway downstream of epidermal growth factor receptor/Akt in human lung carcinomas. Hum Pathol 2011; 42: 214-226.
84. Hiramatsu M, Ninomiya H, Inamura K, Nomura K, Takeuchi K, Satoh Y, Okumura S, Nakagawa K, Yamori T, Matsuura M, Morikawa T and Ishikawa Y. Activation status of receptor tyrosine kinase downstream pathways in primary lung adenocarcinoma with reference of KRAS and EGFR mutations. Lung Cancer 2010; 70: 94-102.
85. Conde E, Angulo B, Tang M, Morente M, Torres-Lanzas J, Lopez-Encuentra A, Lopez-Rios F and Sanchez-Cespedes M. Molecular context of the EGFR mutations: evidence for the activation of mTOR/S6K signaling. Clin Cancer Res 2006; 12: 710-717.
86. McDonald JM, Pelloski CE, Ledoux A, Sun M, Raso G, Komaki R, Wistuba, II, Bekele BN and Aldape K. Elevated phospho-S6 expression is associated with metastasis in adenocarcinoma of the lung. Clin Cancer Res 2008; 14: 7832-7837.
87. Mamane Y, Petroulakis E, Rong L, Yoshida K, Ler LW and Sonenberg N. eIF4E--from translation to transformation. Oncogene 2004; 23: 3172-3179.
88. Ruvinsky I and Meyuhas O. Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem Sci 2006; 31: 342-348.
89. Zhang X, Shu L, Hosoi H, Murti KG and Houghton PJ. Predominant nuclear localization of mammalian target of rapamycin in normal and malignant cells in culture. J Biol Chem 2002; 277: 28127-28134.
90. Dobashi Y, Koyama S, Kanai Y and Tetsuka K. Kinase-driven pathways of EGFR in lung carcinomas: perspectives on targeting therapy. Front Biosci 2011; 16: 1714-1732.
91. La Monica S, Galetti M, Alfieri RR, Cavazzoni A, Ardizzoni A, Tiseo M, Capelletti M, Goldoni M, Tagliaferri S, Mutti A, Fumarola C, Bonelli M, Generali D and Petronini PG. Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines. Biochem Pharmacol 2009; 78: 460-468.
92. Mitsudomi T. Advances in target therapy for lung cancer. Jpn J Clin Oncol 2010; 40: 101-106.
93. An JY, Kim KM, Choi MG, Noh JH, Sohn TS, Bae JM and Kim S. Prognostic role of p-mTOR expression in cancer tissues and metastatic lymph nodes in pT2b gastric cancer. Int J Cancer 2009;
94. Castellvi J, Garcia A, Rojo F, Ruiz-Marcellan C, Gil A, Baselga J and Ramon y Cajal S. Phosphorylated 4E binding protein 1: a hallmark ofcell signaling that correlates with survival in ovarian cancer. Cancer 2006; 107: 1801-1811.
95. Wu C, Wangpaichitr M, Feun L, Kuo MT, Robles C, Lampidis T and Savaraj N. Overcoming cisplatin resistance by mTOR inhibitor in lung cancer. Mol Cancer 2005; 4: 25.
96. Cao C, Subhawong T, Albert JM, Kim KW, Geng L, Sekhar KR, Gi YJ and Lu B. Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res 2006; 66: 10040-10047.
97. Recher C, Dos Santos C, Demur C and Payrastre B. mTOR, a new therapeutic target in acute myeloid leukemia. Cell Cycle 2005; 4: 1540-1549.
98. Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R and Scapozza L. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol 2003; 4: 75-85.
99. Huang S and Houghton PJ. Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr Opin Investig Drugs 2002; 3: 295-304.
100. Woltman AM, van der Kooij SW, Coffer PJ, Offringa R, Daha MR and van Kooten C. Rapamycin specifically interferes with GM-CSF signaling in human dendritic cells, leading to apoptosis via increased p27KIP1 expression. Blood 2003; 101: 1439-1445.
101. Dudkin L, Dilling MB, Cheshire PJ, Harwood FC, Hollingshead M, Arbuck SG, Travis R, Sausville EA and Houghton PJ. Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res 2001; 7: 1758-1764.
102. Dancey JE. Clinical development of mammalian target of rapamycin inhibitors. Hematol Oncol Clin North Am 2002; 16: 1101-1114.
103. Raymond E, Alexandre J, Faivre S, Vera K, Materman E, Boni J, Leister C, Korth-Bradley J, Hanauske A and Armand JP. 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; 22: 2336-2347.
104. Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, Park Y, Liou SH, Marshall B, Boni JP, Dukart G and Sherman ML. 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; 22: 909-918.
105. Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H and Sawyers CL. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/ mTOR. Proc Natl Acad Sci U S A 2001; 98: 10314-10319.
106. Peralba JM, DeGraffenried L, Friedrichs W, Fulcher L, Grunwald V, Weiss G and Hidalgo M. Pharmacodynamic Evaluation of CCI-779, an Inhibitor of mTOR, in Cancer Patients. Clin Cancer Res 2003; 9: 2887-2892.
107. Zhang J, Yang PL and Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 2009; 9: 28-39.
108. Mandal M, Kim S, Younes MN, Jasser SA, El-Naggar AK, Mills GB and Myers JN. The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells. Br J Cancer 2005; 92: 1899-1905.
109. Fu L, Kim YA, Wang X, Wu X, Yue P, Lonial S, Khuri FR and Sun SY. Perifosine inhibits mammalian target of rapamycin signaling through facilitating degradation of major components in the mTOR axis and induces autophagy. Cancer Res 2009; 69: 8967-8976.
110. Fan QW, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D, Shokat KM and Weiss WA. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 2006; 9: 341-349.
111. Bhende PM, Park SI, Lim MS, Dittmer DP and Damania B. The dual PI3K/mTOR inhibitor, NVP -BEZ235, is efficacious against follicular lymphoma. Leukemia 2010; 24: 1781-1784.
112. Mondesire WH, Jian W, Zhang H, Ensor J, Hung MC, Mills GB and Meric-Bernstam F. Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res 2004; 10: 7031-7042.
113. Beuvink I, Boulay A, Fumagalli S, Zilbermann F, Ruetz S, O'Reilly T, Natt F, Hall J, Lane HA and Thomas G. The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 2005; 120: 747-759.
114. Geoerger B, Kerr K, Tang CB, Fung KM, Powell B, Sutton LN, Phillips PC and Janss AJ. Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/ medulloblastoma models as single agent and in combination chemotherapy. Cancer Res 2001; 61: 1527-1532.
115. Goudar RK, Shi Q, Hjelmeland MD, Keir ST, McLendon RE, Wikstrand CJ, Reese ED, Conrad CA, Traxler P, Lane HA, Reardon DA, Cavenee WK, Wang XF, Bigner DD, Friedman HS and Rich JN. 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 2005; 4: 101-112.