The promise of mTOR inhibitors in the treatment of colorectal cancer

Expert Opinion on Investigational Drugs

Volumn 21, Issue 12, 2012, Pages 1775-1788

  Kim, Dae Dong ^a,b   Eng, Cathy ^a  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^b Catholic University of Daegu   (South Korea)

Author keywords

Akt; Cancer; Colorectal cancer; MTOR; PI3K; Rapamycin

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 2 MORPHOLINO 8 PHENYLCHROMONE; 4 DIALLYLAMINOMETHYLENE 1,3,4,7,10,11,12,13,14,15,16,17 DODECAHYDRO 6 HYDROXY 1 METHOXYMETHYL 10,13 DIMETHYL 3,7,17 TRIOXO 2 OXACYCLOPENTA[A]PHENANTHREN 11 YL ACETATE; ADENOSINE TRIPHOSPHATE; AMINO ACID; BEVACIZUMAB; BUPARLISIB; CELL ADHESION MOLECULE; CETUXIMAB; EPIDERMAL GROWTH FACTOR RECEPTOR; EVEROLIMUS; FK 506 BINDING PROTEIN; FLUOROURACIL; FOLINIC ACID; G PROTEIN COUPLED RECEPTOR; GROWTH FACTOR RECEPTOR; INTEGRIN; IRINOTECAN; MACROLIDE; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE; MOLECULAR MARKER; OXALIPLATIN; PHOSPHATIDYLINOSITOL 3 KINASE; PLATELET DERIVED GROWTH FACTOR RECEPTOR; PROTEIN KINASE B; PROTEIN TYROSINE KINASE; RAPAMYCIN; RAPAMYCIN DERIVATIVE; RIDAFOROLIMUS; SOMATOMEDIN C RECEPTOR; TEMSIROLIMUS; UNINDEXED DRUG;

ANTINEOPLASTIC ACTIVITY; CANCER COMBINATION CHEMOTHERAPY; CANCER PATIENT; CANCER RESISTANCE; CELL GROWTH; CELL MEMBRANE; CELL PROLIFERATION; CELL SURVIVAL; CLINICAL TRIAL (TOPIC); COLORECTAL CANCER; DRUG EFFICACY; DRUG INHIBITION; DRUG MECHANISM; DRUG SAFETY; DRUG SOLUBILITY; DRUG STABILITY; DRUG TARGETING; DRUG TOLERABILITY; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MEDIATOR; NONHUMAN; ONCOGENE; OVERALL SURVIVAL; PHASE 2 CLINICAL TRIAL (TOPIC); PROGRESSION FREE SURVIVAL; PROTEIN ANALYSIS; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; TREATMENT DURATION; TREATMENT RESPONSE;

ANIMALS; ANTINEOPLASTIC AGENTS; COLORECTAL NEOPLASMS; HUMANS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS C-AKT; TOR SERINE-THREONINE KINASES;

EID: 84868691651     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2012.721353     Document Type: Review

References (166)

1. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759-67
2. Moran A, Ortega P, de Juan C, et al. Differential colorectal carcinogenesis: molecular basis and clinical relevance. World J Gastrointestin Oncol 2010;2:151-8
3. Walther A, Johnstone E, Swanton C, et al. Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer 2009;9:489-99
4. Tol J, Punt CJ. Monoclonal antibodies in the treatment of metastatic colorectal cancer: a review. Clin Ther 2010;32:437-53
5. Di Fiore F, Blanchard F, Charbonnier F, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer 2007;96:1166-9
6. Lièvre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 2008;26:374-9
7. Van Cutsem E, Kohne CH, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011;29:2011-19
8. Normanno N, Tejpar S, Morgillo F, et al. Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol 2009;6:519-27
9. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70
10. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010;28:1075-83
11. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 2007;7:295-308
12. Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot 1975;28:721-6
13. Martel RR, Klicius J, Galet S. Inhibition of the immune response by rapamycin. a new antifungal antibiotic. Can J Physiol Pharmacol 1977;55:48-51
14. Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 1991;253:905-9
15. Brown EJ, Albers MW, Shin TB, et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 1994;369:756-8
16. Sabatini DM, Erdjument-Bromage H, Lui M, et al. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 1994;78:35-43
17. Sabers CJ, Martin MM, Brunn GJ, et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 1995;270:815-22
18. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006;124:471-84
19. Easton JB, Houghton PJ. mTOR and cancer therapy. Oncogene 2006;25:6436-46
20. Mamane Y, Petroulakis E, LeBacquer O, et al. mTOR, translation initiation, and cancer. Oncogene 2006;25:6416-22
21. Rubio-Viqueira B, Hidalgo M. Targeting mTOR for cancer treatment. Curr Opin Invest Drugs 2006;7:501-12
22. Hudes GR. Targeting mTOR in renal cell carcinoma. Cancer 2009;115:2313-20
23. Huang S, Houghton PJ. Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr Opin Investig Drugs 2002;3:295-304
24. Huang S, Houghton PJ. Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol 2003;3:371-7
25. Nashan B. Early clinical experience with a novel rapamycin derivative. Ther Drug Monit 2002;24:53-8
26. Jacinto E, Hall MN. Tor signalling in bugs, brain and brawn. Nat Rev Mol Cell Biol 2003;4:117-26
27. Shamji AF, Nghiem P, Schreiber SL. Integration of growth factor and nutrient signaling: implications for cancer biology. Mol Cell 2003;12:271-80
28. Beuvink I, Boulay A, Fumagalli S, et al. The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 2005;120:747-59
29. Boulay A, Zumstein-Mecker S, Stephan C, et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 2004;64:252-61
30. O'Reilly T, Vaxelaire J, Muller M, et al. In vivo activity of RAD001, an orally active rapamycin derivative, in experimental tumor models. Proc Am Assoc Cancer Res 2002;43:71
31. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449-56
32. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-81
33. Tsang CK, Qi H, Liu LF, Zheng XF. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today 2007;12:112-24
34. Georgakis GV, Younes A. From Rapa Nui to rapamycin: targeting PI3K/Akt/mTORfor cancer therapy. Exp Rev Anticancer Ther 2006;6:131-40
35. Nozawa H, Watanabe T, Nagawa H. Phosphorylation of ribosomal p70 S6 kinase and rapamycin sensitivity in human colorectal cancer. Cancer Lett 2007;251:105-13
36. Gold PJ, Iriarte D, Arthur J, et al. Phase II trial of RAD001 in patients with refractory metastatic colorectal cancer. J Clin Oncol 2008;27:15s
37. Altomare I, Russell KB, Uronis HE, et al. Phase II trial of bevacizumab plus everolimus for refractory metastatic colorectal cancer. Oncologist. 2011;16:1131-7
38. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007;12:9-22
39. Alessi DR, Pearce LR, Garcia-Martinez JM. New insights into mTOR signaling: mTORC2 and beyond. Sci Signal 2009;2:27
40. Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 2009;10:307-18
41. Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000;103:253-62
42. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009;9:550-62
43. Escobedo JA, Navankasattusas S. Kavanaugh WM, et al. cDNA cloning of a novel 85 kd protein that has SH2 domains and regulates binding of PI3-kinase to the PDGF beta-receptor. Cell 1991;65:75-82
44. Hu P, Margolis B, Skolnik EY, et al. Interaction of hosphatidylinositol 3-kinase-associated p85 with epidermal growth factor and platelet-derived growth factor receptors. Mol Cell Biol 1992;12:981-90
45. Klippel A, Escobedo JA, Fantl WJ, et al. The C terminal SH2 domain of p85 accounts for the high affinity and specificity of the binding of phosphatidylinositol 3-kinase to phosphorylated platelet-derived growth factor beta receptor. Mol Cell Biol 1992;12:1451-9
46. Sarbassov DD, Guertin DA, Ali SM, et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098-101
47. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997;91:231-41
48. Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999;96:857-68
49. Ozes ON, Mayo LD, Gustin JA, et al. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 1999;401:82-5
50. Mayo LD, Donner DB. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 2001;98:11598-603
51. Staal SP. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Nat Acad Sci USA 1987;84:5034-7
52. Garami A, Zwartkruis FJ, Nobukuni T, et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 2003;11:1457-66
53. Tee AR, Manning BD, Roux PP, et al. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol 2003;13:1259-68
54. Zhang Y, Gao X, Saucedo LJ, et al. Rheb is a direct target of the tuberous clerosis tumour suppressor proteins. Nat Cell Biol 2003;5:578-81
55. Inoki K, Li Y, Xu T, et al. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 2003;17:1829-34
56. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7:606-19
57. Inoki K, Li Y, Zhu T, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002;4:648-57
58. Barbet NC, Schneider U, Helliwell SB, et al. TOR controls translation initiation and early G1 progression in yeast. Mol Biol Cell 1996;7:25-42
59. Brunn GJ, Hudson CC, Sekulic A, et al. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 1997;277:99-101
60. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006;5:671-88
61. Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2assembly and Akt/PKB. Mol Cell 2006;22:159-68
62. Kim DH, Sarbassov DD, Ali SM, et al. mTOR interacts with raptor to form a nutrientsensitive complex that signals to the cell growth machinery. Cell 2002;110:163-75
63. Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004;6:1122-8
64. Dann SG, Selvaraj A, Thomas G. mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med 2007;13:252-9
65. Mamane Y, Petroulakis E, LeBacquer O, et al. mTOR, translation initiation and cancer. Oncogene 2006;25:6416-22
66. Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 2009;10:307-18
67. Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 2009;37:217-22
68. Vander Haar E, Lee SI, Bandhakavi S, et al. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 2007;9:316-23
69. Sancak Y, Thoreen CC, Peterson TR, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 2007;25:903-15
70. Wang L, Harris TE, Roth RA, et al. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 2007;282:20036-44
71. Wang L, Harris TE, Lawrence JC Jr. Regulation of proline-rich Akt substrate of 40 kDa (PRAS40) function by mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation. J Biol Chem 2008;283:15619-27
72. Fonseca BD, Smith EM, Lee VH, et al. PRAS40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex. J Biol Chem 2007;282:24514-24
73. 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 2007;282:20329-39
74. Manning BD, Tee AR, Logsdon MN, et al. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002;10:151-62
75. Copp J, Manning G, Hunter T. TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2. Cancer Res 2009;69:1821-7
76. Zbuk KM, Eng C. Cancer phenomics: RET and PTEN as illustrative models. Nat Rev Cancer 2007;7:35-45
77. Schreibman IR, Baker M, Amos C, et al. The hamartomatous polyposis syndromes: a clinical and molecular review. Am J Gastroenterol 2005;100:476-90
78. The COSMIC Catalogue of Somatic Mutations in Cancer database. Cambridge, UK: Wellcome Trust. Available from: http://www.sanger.ac.uk/genetics/CGP/cosmic/
79. Jehan Z, Bavi P, Sultana M, et al. Frequent PIK3CA gene amplification and its clinical significance in colorectal cancer. J Pathol 2009;219:337-46
80. Sartore-Bianchi A, Martini M, Molinari F, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 2009;69:1851-7
81. Keniry M, Parsons R. The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene 2008;27:5477-85
82. Bartholomeusz C, Gonzalez-Angulo AM. Targeting the PI3K signaling pathway in cancer therapy. Expert Opin Ther Targets 2012;16:121-30
83. Hernandez-Aya LF, Gonzalez-Angulo AM. Targeting the phosphatidylinositol 3-kinase signaling pathway in breast cancer. Oncologist 2011;16:404-14
84. Di Cristofano A, Pesce B, Cordon-Cardo C, et al. Pten is essential for embryonic development and tumour suppression. Nat Genet 1998 19:348-55
85. Leslie NR, Foti M. Non-genomic loss of PTEN function in cancer: not in my genes. Trends Pharmacol Sci 2011;32:131-40
86. Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the Pleckstrin homology domain of AKT1 in cancer. Nature 2007;448:439-44
87. Parsons DW, Wang TL, Samuels Y, et al. Colorectal cancer: mutations in a signalling pathway. Nature 2005;436:792
88. Khaleghpour K, Li Y, Banville D, et al. Involvement of the PI 3-kinase signaling pathway in progression of colon adenocarcinoma. Carcinogenesis 2004;25:241-8
89. Vlahos CJ, Matter WF, Hui KY, et al. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 1994;269:5241-8
90. Powis G, Bonjouklian R, Berggren MM, et al. Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res 1994;54:2419-23
91. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009;9:550-62
92. Markus HM, Annett M, Erika B, et al. Selective PI3K inhibition by BKM120 and BEZ235 alone or in combination with chemotherapy in wild-type and mutated human gastrointestinal cancer cell lines. J Clin Oncol 2012;30: abstract 522
93. Gills JJ, Dennis PA. Perifosine: update on a novel Akt inhibitor. Curr Oncol Rep 2009;11:102-10
94. Bendell JC, Nemunaitis J, Vukelja SJ, et al. Randomized placebo-controlled phase II trial of perifosine plus capecitabine as second-or third-line therapy in patients with metastatic colorectal cancer. J Clin Oncol 2011;29:4394-400
95. Johanna C. Bendell, Thomas J. et al. Results of the X-PECT study: A phase III randomized double-blind, placebo-controlled study of perifosine plus capecitabine (P-CAP) versus placebo plus capecitabine (CAP) in patients (pts) with refractory metastatic colorectal cancer (mCRC). J Clin Oncol 2012;30: abstract LBA3501
96. Lee JT, Li L, Brafford PA, et al. PLX4032, a potent inhibitor of the B-Raf V600E oncogene, selectively inhibits V600E-positive melanomas. Pigment Cell Melanoma Res 2010;23:820-7
97. Yang H, Higgins B, Kolinsky K, et al. Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res 2012;72:779-89
98. Seufferlein T, Rozengurt E. Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells. Cancer Res 1996;56:3895-7
99. Grewe M, Gansauge F, Schmid RM, et al. Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells. Cancer Res 1999;59:3581-7
100. Fasolo A, Sessa C. Current and future directions in mammalian target of rapamycin inhibitors development. Expert Opin Investig Drugs 2011;20:381-94
101. Raymond E, Alexandre J, Faivre S, et al. Safety and pharmacokinetics of escalated doses of weekly IV infusion of CCI-779, a novel mTOR inhibitor, in patient with cancer. J Clin Oncol 2004;222336-47
102. Tabernero J, Rojo F, Calvo E, et al. Dose-and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 2008;26:1603-10
103. O'Donnell A, Faivre S, Burris HA III, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 2008;26:1588-95
104. Fuchs CS, Tabernero JM, Hwang J, et al. Multicenter phase II study of RAD001 in patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). J Clin Oncol 2009;27: abstract No:446
105. Hamilton SR, Vogelstein B, Kudo S, et al. Tumours of the colon and rectum. In: Hamilton SR, Aaltonen L, editors, Pathology and genetics of tumours of the digestive system. World Health Organization classification of tumours. IARC Press, Lyon; 2001. p. 104-19
106. Vignot S, Faivre S. Aguirre D, et al. mTOR targeted therapy of cancer with rapamycin derivatives. Ann Oncol 2005;16:525-37
107. O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66:1500-8
108. Buck E, Eyzaguirre A, Brown E, et al. Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol Cancer Ther 2006;5:2676-84
109. Zhang YJ, Fang JY, Sun DF, et al. Synergistic effect of rapamycin (RPM) and PD98059 on cell cycle and mTOR signal transduction in human colorectal cancer cells. Zhonghua Zhong Liu Za Zhi 2007;29:889-93
110. Bullock KE, Hurwitz HI, Uronis HE, et al. Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC). J Clin Oncol 2009;27: abstract 4080
111. Brian MW, Kimmie Ng, Andrew XZ, et al. Multicenter phase Ib/II study of everolimus (RAD001) and tivozanib (AV-951) in patients with refractory, metastatic colorectal cancer. J Clin Oncol 2012;30: abstract 560
112. Bianco R, Garofalo S, Rosa R, et al. Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs. Br J Cancer 2008;98:923-30
113. Townsend AR, Pirc L, Hardingham J, et al. A phase Ib/II study of second-line therapy with panitumumab, irinotecan, and everolimus (PIE) in metastatic colorectal cancer with KRAS wild type (WT). J Clin Oncol 2011;29: abstract TPS162
114. Foster DA, Toschi A. Targeting mTOR with rapamycin: one dose does not fit all. Cell Cycle 2009;8:1026-9
115. Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006;22:159-68
116. Intellikine. Dose Escalation Study of INK128 in Subjects With Advanced Cancer ClinicalTrials.gov Identifier: NCT01058707
117. Fasolo A, Sessa C. mTOR inhibitors in the treatment of cancer. Expert Opin Investig Drugs 2008;17:1717-34
118. Roper J, Richardson MP, Wang WV, et al. The dual PI3K/mTOR inhibitor NVP-BEZ235 induces tumor regression in a genetically engineered mouse model of PIK3CA wild-type colorectal cancer. PLoS One 2011;6:25132
119. Lane H. The potential of mTOR inhibitors for the treatment of human cancers. 98th AACR Annual Meeting 2007: Abstract SY21-01
120. Murphy JD, Spalding AC, Somnay YR, et al. Inhibition of mTOR radiosensitizes soft tissue sarcoma and tumor vasculature. Clin Cancer Res 2009;15:589-96
121. Manegold PC, Paringer C, Kulka U, et al. Antiangiogenic therapy with mammalian target of rapamycin inhibitor RAD001 (Everolimus) increases radiosensitivity in solid cancer. Clin Cancer Res 2008;14:892-900
122. Faivre S, Djelloul S, Raymond E. New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors. Semin Oncol 2006;33:407-20
123. Espina V, Geho D, Mehta AI, et al. Pathology of the future: molecular profiling for targeted therapy. Cancer Invest 2005;23:36-46
124. Wang LH, Chan JL, Li W. Rapamycin together with herceptin significantly increased anti-tumor efficacy compared to either alone in ErbB2 overexpressing breast cancer cells. Int J Cancer 2007;121:2911-18
125. Tortora G, Bianco R, Daniele G, et al. Overcoming resistance to molecularly targeted anticancer therapies: rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies. Drug Resist Updates 2007;10:81-100
126. Zhang YJ, Tian XQ, Sun DF, et al. Combined inhibition of MEK and mTOR signaling inhibits initiation and progression of colorectal cancer. Cancer Invest 2009;27:273-85
127. Casa AJ, Dearth RK, Litzenburger BC, et al. The type I insulin-like growth factor receptor pathway: a key player in cancer therapeutic resistance. Front Biosci 2008;13:3273-87
128. Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004;6:117-27
129. Lu CH, Wyszomierski SL, Tseng LM, et al. Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin Cancer Res 2007;13:5883-8
130. El-Hashemite N, Walker V, Zhang H, et al. Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. Cancer Res 2003;63:5173-7
131. Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 2002;22:7004-14
132. Humar R, Kiefer FN, Berns H, et al. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J 2002;16:771-80
133. Wan X, Harkavy B, Shen N, et al. Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 2007;26:1932-40
134. Hart L, Burris HA, Infante JR, et al. mTOR inhibitor everolimus (Ev) and IGFR inhibitor OSI-906 (OSI) for the treatment of patients (pts) with refractory metastatic colorectal cancer (mCRC): A Sarah Cannon Research Institute phase I trial. J Clin Oncol 2011;29: abstract e14054
135. Quek R, Wang Q, Morgan JA, et al. Combination mTOR and IGF-1R inhibition: phase I trial of everolimus and figitumumab in patients with advanced sarcomas and other solid tumors. Clin Cancer Res 2011;17:871-9
136. Aissat N, Le Tourneau C, Ghoul A, et al. Antiproliferative effects of rapamycin as a single agent and in combination with carboplatin and paclitaxel in head and neck cancer cell lines. Cancer Chemother Pharmacol 2008;62:305-13
137. Davies JM, McRee AJ, Sanoff HK, et al. Phase I study of the combination of everolimus (RAD001) with 5FU/LV in patients with refractory solid malignancies. J Clin Oncol 2011;29:abstract 512
138. Glynn WG, John RW, Kimberly J, et al. Phase I study of mFOLFOX-6, bevacizumab, and mTOR inhibitor RAD001 as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2012;30:abstract 600
139. Sharma S, Reid T, Hoosen S, et al. Phase I study of RAD001 (everolimus), cetuximab, and irinotecan as second-line therapy in metastatic colorectal cancer (mCRC). J Clin Oncol 2009;27:abstract e15115
140. Shahda S, Yu M, Picus J, et al. Phase I study of everolimus (RAD001) with irinotecan (Iri) and cetuximab (C) in second-line metastatic colorectal cancer (mCRC): Hoosier Oncology Group GI05-102-Final report. J Clin Oncol 2011;29:abstract 3587
141. Lu R, Wang X, Chen ZF, et al. Inhibition of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway decrease DNA methylation in colon cancer cells. J Biol Chem 2007;282:12249-59
142. Rodriguez J, Frigola J, Vendrell E, et al. Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. Cancer Res 2006;66:8462-8
143. Wilson AS, Power BE, Molloy PL. DNA hypomethylation and human diseases. Biochim Biophys Acta 2007;1775:138-62
144. Goel A, Arnold CN, Niedzwiecki D, et al. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res 2004;64:3014-21
145. Plumb JA, Strathdee G, Sludden J, et al. Reversal of drug resistance in human tumor xenografts by 2¢-deoxy-5-azacytidineinduced demethylation of the hMLH1 gene promoter. Cancer Res 2000;60:6039-44
146. Haney SA. Expanding the repertoire of RNA interference screens for developing new anticancer drug targets. Expert Opin Ther Targets 2007;11:1429-41
147. Micklem DR, Lorens JB. RNAi screening for therapeutic targets in human malignancies. Curr Pharm Biotechnol 2007;8:337-43
148. Hidalgo M, Buckner JC, Erlichman C, et al. A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every2 weeks to patients with advanced cancer. Clin Cancer Res 2006;12:5755-63
149. O'Donnell A, Faivre S, Burris HA 3rd, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 2008;26:1588-95
150. Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell. 2005;8:179-83
151. Breuleux M, Klopfenstein M, Stephan C, et al. Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition. Mol Cancer Ther 2009;8:742-53
152. Squillace RM, Miller D, Cookson M, et al. Antitumor activity of ridaforolimus and potential cell-cycle determinants of sensitivity in sarcoma and endometrial cancer models. Mol Cancer Ther 2011;10:1959-68
153. O'Reilly T, McSheehy PM. Biomarker development for the clinical activity of the mTOR inhibitor everolimus (RAD001): processes, limitations, and further proposals. Transl Oncol 2010;3:65-79
154. Di Nicolantonio F, Arena S, Tabernero J, et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest 2010;20:2858-66
155. Meric-Bernstam F, Akcakanat A, Chen H, et al. PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors. Clin Cancer Res 2012;18:1777-89
156. Garcia-Barros M, Paris F, Cordon-Cardo C, et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 2003;300:1155-9
157. Camphausen K, Tofilon PJ. Combining radiation and molecular targeting in cancer therapy. Cancer Biol Ther 2004;3:247-50
158. Gorski DH, Beckett MA, Jaskowiak NT, et al. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 1999;59:3374-8
159. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003;3:401-10
160. Lee CG, Heijn M, di Tomaso E, et al. Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 2000;60:5565-70
161. Jain RK. Normalizing tumor vasculature with antiangiogenic therapy: a new paradigm for combination therapy. Nat Med 2001;7:987-9
162. Kerbel RS. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 2006;312:1171-5
163. Manegold PC, Paringer C, Kulka U, et al. Antiangiogenic therapy with mammalian target of rapamycin inhibitor RAD001 (Everolimus) increases radiosensitivity in solid cancer. Clin Cancer Res 2008;14:892-900
164. Kim KW, Mutter RW, Cao C, et al. Autophagy for cancer therapy through inhibition of pro-apoptotic proteins and mammalian target of rapamycin signaling. J Biol Ch 2006;281:36883-90
165. Paglin S, Lee NY, Nakar C, et al. Rapamycin-sensitive pathway regulates mitochondrial membrane potential, auto-phagy, and survival in irradiated MCF-7 cells. Cancer Res 2005;65:11061-70
166. Shinohara ET, Cao C, Niermann K, et al. Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene 2005;24:5414-22