Role of mTOR in anticancer drug resistance: Perspectives for improved drug treatment

Drug Resistance Updates

Volumn 11, Issue 3, 2008, Pages 63-76

  Jiang, Bing Hua ^a   Liu, Ling Zhi ^a  

^a WEST VIRGINIA UNIVERSITY   (United States)

Author keywords

AKT; AP 23573; CCI 779; Drug resistance; MAP kinase; mTOR; Neurofibromatosis 1; p70S6K1; PI3K; RAD001 (everolimus); VEGF

Indexed keywords

4 (3 BROMOANILINO) 6,7 DIMETHOXYQUINAZOLINE; AP 23573; CYCLIN A; CYCLIN DEPENDENT KINASE 1; CYCLIN DEPENDENT KINASE 2; CYCLIN DEPENDENT KINASE INHIBITOR; CYCLIN DEPENDENT KINASE INHIBITOR 1; CYCLIN DEPENDENT KINASE INHIBITOR 1B; DNA DIRECTED RNA POLYMERASE; DNA DIRECTED RNA POLYMERASE III; EVEROLIMUS; GEFITINIB; HYPOXIA INDUCIBLE FACTOR 1ALPHA; INITIATION FACTOR 4E; INITIATION FACTOR 4E BINDING PROTEIN 1; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MESSENGER RNA; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE 3; MYC PROTEIN; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B; RAF PROTEIN; RAPAMYCIN; RAS PROTEIN; RETINOBLASTOMA PROTEIN; S6 KINASE; TEMSIROLIMUS; UNINDEXED DRUG; VASCULOTROPIN;

ANGIOGENESIS; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CHEMOTHERAPY; CANCER GROWTH; CANCER RESISTANCE; CELL CYCLE PROGRESSION; CELL SURVIVAL; HUMAN; METASTASIS; MOLECULAR INTERACTION; ONCOGENE C MYC; PRIORITY JOURNAL; PROTEIN SYNTHESIS; REGULATORY MECHANISM; SIGNAL TRANSDUCTION;

ANTINEOPLASTIC AGENTS; APOPTOSIS; CELL CYCLE; DRUG RESISTANCE, NEOPLASM; HUMANS; NEOPLASMS; PROTEIN BIOSYNTHESIS; PROTEIN CONFORMATION; PROTEIN KINASE INHIBITORS; PROTEIN KINASES; SIGNAL TRANSDUCTION;

EID: 46149092748     PISSN: 13687646     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.drup.2008.03.001     Document Type: Article

References (170)

1. Abraham R.T. Identification of TOR signaling complexes: more TORC for the cell growth engine. Cell 111 (2002) 9-12
2. Avdulov S., Li S., Michalek V., Burrichter D., Peterson M., Perlman D.M., et al. Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell 5 (2004) 553-563
3. Baker G.L., Landis M.W., and Hinds P.W. Multiple functions of D-type cyclins can antagonize pRb-mediated suppression of proliferation. Cell Cycle 4 (2005) 330-338
4. Bamford S., Dawson E., Forbes S., Clements J., Pettett R., Dogan A., et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br. J. Cancer 91 (2004) 355-358
5. Bauer S., Duensing A., Demetri G.D., and Fletcher J.A. KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene 26 (2007) 7560-7568
6. Beeram M., Tan Q.T., Tekmal R.R., Russell D., Middleton A., and De Graffenried L.A. Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling. Ann. Oncol. 18 (2007) 1323-1328
7. Berns K., Horlings H.M., Hennessy B.T., Madiredjo M., Hijmans E.M., Beelen K., et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12 (2007) 395-402
8. Beuvink I., Boulay A., Fumagalli S., Zilbermann F., Ruetz S., O'Reilly T., Natt F., et al. The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 120 (2005) 747-759
9. Bjornsti M.A., and Houghton P.J. The TOR pathway: a target for cancer therapy. Nat. Rev. Cancer 4 (2004) 335-348
10. Blume-Jensen P., and Hunter T. Oncogenic kinase signalling. Nature 411 (2001) 355-365
11. Bortul R., Tazzari P.L., Cappellini A., Tabellini G., Billi A.M., Bareggi R., et al. Constitutively active Akt1 protects HL60 leukemia cells from TRAIL-induced apoptosis through a mechanism involving NF-kappaB activation and cFLIP(L) up-regulation. Leukemia 17 (2003) 379-389
12. Brass N., Heckel D., Sahin U., Pfreundschuh M., Sybrecht G.W., and Meese E. Translation initiation factor eIF-4gamma is encoded by an amplified gene and induces an immune response in squamous cell lung carcinoma. Hum. Mol. Genet. 6 (1997) 33-39
13. Brown E.J., Albers M.W., Shin T.B., Ichikawa K., Keith C.T., Lane W.S., and Schreiber S.L. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369 (1994) 756-758
14. Broxterman H.J., and Georgopapadakou N.H. Anticancer therapeutics: a surge of new developments increasingly target tumor and stroma. Drug Resist. Update 10 (2007) 182-193
15. Bruwer A., Bargen J.A., and Kierland R.R. Surface pigmentation and generalized intestinal polyposis (Peutz-Jeghers syndrome). Proc. Staff Meet. Mayo Clin. 29 (1954) 168-171
16. Campbell R.A., Bhat-Nakshatri P., Patel N.M., Constantinidou D., Ali S., and Nakshatri H. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J. Biol. Chem. 276 (2001) 9817-9824
17. Cantley L.C. The phosphoinositide 3-kinase pathway. Science 296 (2002) 1655-1657
18. Castellvi J., Garcia A., Rojo F., Ruiz-Marcellan C., Gil A., Baselga J., and Cajal S. Phosphorylated 4E binding protein 1: a hallmark of cell signaling that correlates with survival in ovarian cancer. Cancer 107 (2006) 1801-1811
19. Chan S., Scheulen M.E., Johnston S., Mross K., Cardoso F., Dittrich C., et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J. Clin. Oncol. 23 (2005) 5314-5322
20. Chen C.N., Hsieh F.J., Cheng Y.M., Lee P.H., and Chang K.J. Expression of eukaryotic initiation factor 4E in gastric adenocarcinoma and its association with clinical outcome. J. Surg. Oncol. 86 (2004) 22-27
21. Chen X., Thakkar H., Tyan F., Gim S., Robinson H., Lee C., et al. Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer. Oncogene 20 (2001) 6073-6083
22. 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
23. Chollet P., Abrial C., Tacca O., Mouret-Reynier M.A., Leheurteur M., Durando X., and Cure H. Mammalian target of rapamycin inhibitors in combination with letrozole in breast cancer. Clin. Breast Cancer 7 (2006) 336-338
24. Cichowski K., and Jacks T. NF1 tumor suppressor gene function: narrowing the GAP. Cell 104 (2001) 593-604
25. Clark A.S., West K., Streicher S., and Dennis P.A. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol. Cancer Ther. 1 (2002) 707-717
26. Cloughesy T.F., Yoshimoto K., Nghiemphu P., Brown K., Dang J., Zhu S., et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med. 5 (2008) e8
27. Couch F.J., Wang X.Y., Wu G.J., Qian J., Jenkins R.B., and James C.D. Localization of PS6K to chromosomal region 17q23 and determination of its amplification in breast cancer. Cancer Res. 59 (1999) 1408-1411
28. Crew J.P., Fuggle S., Bicknell R., Cranston D.W., De Benedetti A., and Harris A.L. Eukaryotic initiation factor-4E in superficial and muscle invasive bladder cancer and its correlation with vascular endothelial growth factor expression and tumour progression. Br. J. Cancer 82 (2000) 161-166
29. Cui Y., Parra I., Zhang M., Hilsenbeck S.G., Tsimelzon A., Furukawa T., et al. Elevated expression of mitogen-activated protein kinase phosphatase 3 in breast tumors: a mechanism of tamoxifen resistance. Cancer Res. 66 (2006) 5950-5959
30. Datta S.R., Brunet A., and Greenberg M.E. Cellular survival: a play in three Akts. Genes Dev. 13 (1999) 2905-2927
31. DeFatta R.J., and De Benedetti A. Translational upregulation of yes accompanies eIF4E-mediated oncogenic transformation. Int. J. Oncol. 23 (2003) 1709-1713
32. DeGraffenried L.A., Friedrichs W.E., Russell D.H., Donzis E.J., Middleton A.K., Silva J.M., Roth R.A., and Hidalgo M. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt activity. Clin. Cancer Res. 10 (2004) 8059-8067
33. Dengler J., von Bubnoff N., Decker T., Peschel C., and Duyster J. Combination of imatinib with rapamycin or RAD001 acts synergistically only in Bcr-Abl-positive cells with moderate resistance to imatinib. Leukemia 19 (2005) 1835-1838
34. Dennis P.B., Jaeschke A., Saitoh M., Fowler B., Kozma S.C., and Thomas G. Mammalian TOR: a homeostatic ATP sensor. Science 294 (2001) 1102-1105
35. Dennis P.B., Pullen N., Kozma S.C., and Thomas G. The principal rapamycin-sensitive p70(s6k) phosphorylation sites, T-229 and T-389, are differentially regulated by rapamycin-insensitive kinase kinases. Mol. Cell Biol. 16 (1996) 6242-6251
36. Dudkin L., Dilling M.B., Cheshire P.J., Harwood F.C., Hollingshead M., Arbuck S.G., et al. Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin. Cancer Res. 7 (2001) 1758-1764
37. Eberle J., Fecker L.F., Bittner J.U., Orfanos C.E., and Geilen C.C. Decreased proliferation of human melanoma cell lines caused by antisense RNA against translation factor eIF-4A1. Br. J. Cancer 86 (2002) 1957-1962
38. Eberle J., Krasagakis K., and Orfanos C.E. Translation initiation factor eIF-4A1 mRNA is consistently overexpressed in human melanoma cells in vitro. Int. J. Cancer 71 (1997) 396-401
39. Eberle J., Kurbanov B.M., Hossini A.M., Trefzer U., and Fecker L.F. Overcoming apoptosis deficiency of melanoma-Hope for new therapeutic approaches. Drug Resist. Update 10 (2007) 218-234
40. Eckstein N., Servan K., Girard L., Cai D., von Jonquieres G., Jaehde U., et al. Epidermal growth factor receptor pathway analysis identifies amphiregulin as a key factor for cisplatin resistance of human breast cancer cells. J. Biol. Chem. 283 (2008) 739-750
41. Engelman J.A., Luo J., and Cantley L.C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7 (2006) 606-619
42. Estrela J.M., Ortega A., and Obrador E. Glutathione in cancer biology and therapy. Crit Rev. Clin. Lab Sci. 43 (2006) 143-181
43. Faivre S., Kroemer G., and Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat. Rev. Drug Discov. 5 (2006) 671-688
44. Fang J., Meng Q., Vogt P.K., Zhang R., and Jiang B.H. A downstream kinase of the mammalian target of rapamycin, p70S6K1, regulates human double minute 2 protein phosphorylation and stability. J. Cell Physiol. 209 (2006) 261-265
45. Fang J., Xia C., Cao Z., Zheng J.Z., Reed E., and Jiang B.H. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB J. 19 (2005) 342-353
46. Feng Z., Zhang H., Levine A.J., and Jin S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl. Acad. Sci. U.S.A. 102 (2005) 8204-8209
47. Fraser M., Bai T., and Tsang B.K. Akt promotes cisplatin resistance in human ovarian cancer cells through inhibition of p53 phosphorylation and nuclear function. Int. J. Cancer 122 (2008) 534-546
48. Frogne T., Jepsen J.S., Larsen S.S., Fog C.K., Brockdorff B.L., and Lykkesfeldt A.E. Antiestrogen-resistant human breast cancer cells require activated protein kinase B/Akt for growth. Endocr. Relat. Cancer 12 (2005) 599-614
49. Frost P., Moatamed F., Hoang B., Shi Y., Gera J., Yan H., 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
50. Fojo T. Multiple paths to a drug resistance phenotype: mutations, translocations, deletions and amplification of coding genes or promoter regions, epigenetic changes and microRNAs. Drug Resist. Update 10 (2007) 59-67
51. Fukuchi-Shimogori T., Ishii I., Kashiwagi K., Mashiba H., Ekimoto H., and Igarashi K. Malignant transformation by overproduction of translation initiation factor eIF4G. Cancer Res. 57 (1997) 5041-5044
52. Gagnon V., Mathieu I., Sexton E., Leblanc K., and Asselin E. AKT involvement in cisplatin chemoresistance of human uterine cancer cells. Gynecol. Oncol. 94 (2004) 785-795
53. Galanis E., Buckner J.C., Maurer M.J., Kreisberg J.I., Ballman K., Boni 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
54. Gao N., Flynn D.C., Zhang Z., Zhong X.S., Walker V., Liu K.J., Shi X., and Jiang B.H. G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells. Am. J. Physiol. Cell. Physiol. 287 (2004) C281-C291
55. Gao N., Shen L., Zhang Z., Leonard S.S., He H., Zhang X.G., Shi X., and Jiang B.H. Arsenite induces HIF-1alpha and VEGF through PI3K, Akt and reactive oxygen species in DU145 human prostate carcinoma cells. Mol. Cell Biochem. 255 (2004) 33-45
56. Gao X., Zhang Y., Arrazola P., Hino O., Kobayashi T., Yeung R.S., Ru B., and Pan D. Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat. Cell Biol. 4 (2002) 699-704
57. Garnett M.J., and Marais R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6 (2004) 313-319
58. Garnett M.J., Rana S., Paterson H., Barford D., and Marais R. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol. Cell 20 (2005) 963-969
59. Granville C.A., Memmott R.M., Gills J.J., and Dennis P.A. Handicapping the race to develop inhibitors of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway. Clin. Cancer Res. 12 (2006) 679-689
60. Grolleau A., Wietzerbin J., and Beretta L. Defect in the regulation of 4E-BP1 and 2, two repressors of translation initiation, in the retinoid acid resistant cell lines, NB4-R1 and NB4-R2. Leukemia 14 (2000) 1909-1914
61. 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
62. Han S.W., Hwang P.G., Chung D.H., Kim D.W., Im S.A., Kim Y.T., et al. Epidermal growth factor receptor (EGFR) downstream molecules as response predictive markers for gefitinib (Iressa, ZD1839) in chemotherapy-resistant non-small cell lung cancer. Int. J. Cancer 113 (2005) 109-115
63. Haruta T., Uno T., Kawahara J., Takano A., Egawa K., Sharma P.M., et al. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol. Endocrinol. 14 (2000) 783-794
64. 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
65. Hay N., and Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 18 (2004) 1926-1945
66. Hemminki A., Markie D., Tomlinson I., Avizienyte E., Roth S., Loukola A., et al. A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391 (1998) 184-187
67. Hennessy B.T., Smith D.L., Ram P.T., Lu Y., and Mills G.B. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug Discov. 4 (2005) 988-1004
68. Holz M.K., and Blenis J. Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J. Biol. Chem. 280 (2005) 26089-26093
69. Houshmandi S.S., and Gutmann D.H. All in the family: using inherited cancer syndromes to understand de-regulated cell signaling in brain tumors. J. Cell Biochem. 102 (2007) 811-819
70. Huang S., Bjornsti M.A., and Houghton P.J. Rapamycins: mechanism of action and cellular resistance. Cancer Biol. Ther. 2 (2003) 222-232
71. Huang S., Shu L., Dilling M.B., Easton J., Harwood F.C., Ichijo H., and Houghton P.J. Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1). Mol. Cell 11 (2003) 1491-1501
72. Ilyin G.P., Glaise D., Gilot D., Baffet G., and Guguen-Guillouzo C. Regulation and role of p21 and p27 cyclin-dependent kinase inhibitors during hepatocyte differentiation and growth. Am. J. Physiol Gastrointest. Liver Physiol. 285 (2003) G115-G127
73. Inoki K., Corradetti M.N., and Guan K.L. Dysregulation of the TSC-mTOR pathway in human disease. Nat. Genet. 37 (2005) 19-24
74. Inoki K., Zhu T., and Guan K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115 (2003) 577-590
75. Jacinto E., and Hall M.N. Tor signalling in bugs, brain and brawn. Nat. Rev. Mol. Cell Biol. 4 (2003) 117-126
76. James M.J., and Zomerdijk J.C. Phosphatidylinositol 3-kinase and mTOR signaling pathways regulate RNA polymerase I transcription in response to IGF-1 and nutrients. J. Biol. Chem. 279 (2004) 8911-8918
77. 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. 10 (2005) 479-498
78. Jastrzebski K., Hannan K.M., Tchoubrieva E.B., Hannan R.D., and Pearson R.B. Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function. Growth Factors 25 (2007) 209-226
79. Jenne D.E., Reimann H., Nezu J., Friedel W., Loff S., Jeschke R., et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat. Genet. 18 (1998) 38-43
80. Jiang B.H., and Liu L.Z. PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim. Biophys. Acta 1784 (2008) 150-158
81. Jimeno A., Kulesza P., Wheelhouse J., Chan A., Zhang X., Kincaid E., et al. Dual EGFR and mTOR targeting in squamous cell carcinoma models, and development of early markers of efficacy. Br. J. Cancer 96 (2007) 952-959
82. 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
83. Johnson S.M., Grosshans H., Shingara J., Byrom M., Jarvis R., Cheng A., et al. RAS is regulated by the let-7 microRNA family. Cell 120 (2005) 635-647
84. Katayama K., Yoshioka S., Tsukahara S., Mitsuhashi J., and Sugimoto Y. Inhibition of the mitogen-activated protein kinase pathway results in the down-regulation of P-glycoprotein. Mol. Cancer Ther. 6 (2007) 2092-2102
85. Kawamata S., Sakaida H., Hori T., Maeda M., and Uchiyama T. The upregulation of p27Kip1 by rapamycin results in G1 arrest in exponentially growing T-cell lines. Blood 91 (1998) 561-569
86. Kisucka J., Barancik M., Bohacova V., and Breier A. Reversal effect of specific inhibitors of extracellular-signal regulated protein kinase pathway on P-glycoprotein mediated vincristine resistance of L1210 cells. Gen. Physiol. Biophys. 20 (2001) 439-444
87. Kolfschoten I.G., van Leeuwen B., Berns K., Mullenders J., Beijersbergen R.L., Bernards R., et al. A genetic screen identifies PITX1 as a suppressor of RAS activity and tumorigenicity. Cell 121 (2005) 849-858
88. Kunz J., Henriquez R., Schneider U., Deuter-Reinhard M., Movva N.R., and Hall M.N. Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73 (1993) 585-596
89. Lee Jr. J.T., Steelman L.S., and McCubrey J.A. Phosphatidylinositol 3′-kinase activation leads to multidrug resistance protein-1 expression and subsequent chemoresistance in advanced prostate cancer cells. Cancer Res. 64 (2004) 8397-8404
90. Lee S., Choi E.J., Jin C., and Kim D.H. Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol. Oncol. 97 (2005) 26-34
91. Lee T.J., Lee J.T., Park J.W., and Kwon T.K. Acquired TRAIL resistance in human breast cancer cells are caused by the sustained cFLIP(L) and XIAP protein levels and ERK activation. Biochem. Biophys. Res. Commun. 351 (2006) 1024-1030
92. Li B., Chang C.M., Yuan M., McKenna W.G., and Shu H.K. Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas. Cancer Res. 63 (2003) 7443-7450
93. Li D., Shimamura T., Ji H., Chen L., Haringsma H.J., McNamara K., et al. Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy. Cancer Cell 12 (2007) 81-93
94. Lin H.L., Lui W.Y., Liu T.Y., and Chi C.W. Reversal of Taxol resistance in hepatoma by cyclosporin A: involvement of the PI-3 kinase-AKT 1 pathway. Br. J. Cancer 88 (2003) 973-980
95. Lin J.C., Chang S.Y., Hsieh D.S., Lee C.F., and Yu D.S. Modulation of mitogen-activated protein kinase cascades by differentiation-1 protein: acquired drug resistance of hormone independent prostate cancer cells. J. Urol. 174 (2005) 2022-2026
96. Liu L.Z., Hu X.W., Xia C., He J., Zhou Q., Shi X., Fang J., and Jiang B.H. Reactive oxygen species regulate epidermal growth factor-induced vascular endothelial growth factor and hypoxia-inducible factor-1alpha expression through activation of AKT and P70S6K1 in human ovarian cancer cells. Free Radic. Biol. Med. 41 (2006) 1521-1533
97. Liu L.Z., Zhou X.D., Qian G., Shi X., Fang J., and Jiang B.H. AKT1 amplification regulates cisplatin resistance in human lung cancer cells through the mammalian target of rapamycin/p70S6K1 pathway. Cancer Res. 67 (2007) 6325-6332
98. Liu S.Q., Yu J.P., Yu H.G., et al. Activation of Akt and ERK signalling pathways induced by etoposide confer chemoresistance in gastric cancer cells. Dig. Liver Dis. 38 (2006) 310-318
99. Liu Y., Chen L., Ko T.C., Fields A.P., and Thompson E.A. Evi1 is a survival factor which conveys resistance to both TGFbeta- and taxol-mediated cell death via PI3K/AKT. Oncogene 25 (2006) 3565-3575
100. Lu C.H., Wyszomierski S.L., Tseng L.M., Sun M.H., Lan K.H., Neal C.L., et al. Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin. Cancer Res. 13 (2007) 5883-5888
101. Madhusudan S., and Middleton M.R. The emerging role of DNA repair proteins as predictive, prognostic and therapeutic targets in cancer. Cancer Treat. Rev. 31 (2005) 603-617
102. Mamane Y., Petroulakis E., LeBacquer O., and Sonenberg N. mTOR, translation initiation and cancer. Oncogene 25 (2006) 6416-6422
103. Martin M.E., Perez M.I., Redondo C., Alvarez M.I., Salinas M., and Fando J.L. 4E binding protein 1 expression is inversely correlated to the progression of gastrointestinal cancers. Int. J. Biochem. Cell Biol. 32 (2000) 633-642
104. Mayer C., and Grummt I. Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene 25 (2006) 6384-6391
105. Mayer C., Zhao J., Yuan X., and Grummt I. mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev. 18 (2004) 423-434
106. McClusky D.R., Chu Q., Yu H., Debenedetti A., Johnson L.W., Meschonat C., et al. A prospective trial on initiation factor 4E (eIF4E) overexpression and cancer recurrence in node-positive breast cancer. Ann. Surg. 242 (2005) 584-590
107. McCubrey J.A., Steelman L.S., Abrams S.L., Lee J.T., Chang F., Bertrand F.E., et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv. Enzyme Regul. 46 (2006) 249-279
108. McCubrey J.A., Steelman L.S., Chappell W.H., Abrams S.L., Wong E.W., Chang F., et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim. Biophys. Acta 1773 (2007) 1263-1284
109. Meng Q., Xia C., Fang J., Rojanasakul Y., and Jiang B.H. Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. Cell Signal. 18 (2006) 2262-2271
110. Merritt J.L., Davis D.M., Pittelkow M.R., and Babovic-Vuksanovic D. Extensive acrochordons and pancreatic islet-cell tumors in tuberous sclerosis associated with TSC2 mutations. Am. J. Med. Genet. A 140 (2006) 1669-1672
111. Mohi M.G., Boulton C., Gu T.L., Sternberg D.W., Neuberg D., Griffin J.D., et al. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc. Natl. Acad. Sci. U.S.A. 101 (2004) 3130-3135
112. Mollinedo F., and Gajate C. Fas/CD95 death receptor and lipid rafts: new targets for apoptosis-directed cancer therapy. Drug Resist. Update 9 (2006) 51-73
113. Mondesire W.H., Jian W., Zhang H., Ensor J., Hung M.C., et al. Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin. Cancer Res. 10 (2004) 7031-7042
114. Moretti L., Yang E.S., Kim K.W., and Lu B. Autophagy signaling in cancer and its potential as novel target to improve anticancer therapy. Drug Resist. Update 10 (2007) 135-143
115. Nathan C.O., Franklin S., Abreo F.W., Nassar R., De Benedetti A., and Glass J. Analysis of surgical margins with the molecular marker eIF4E: a prognostic factor in patients with head and neck cancer. J. Clin. Oncol. 17 (1999) 2909-2914
116. Neri L.M., Borgatti P., Tazzari P.L., Bortul R., Cappellini A., Tabellini G., et al. The phosphoinositide 3-kinase/AKT1 pathway involvement in drug and all-trans-retinoic acid resistance of leukemia cells. Mol. Cancer Res. 1 (2003) 234-246
117. Neshat M.S., Mellinghoff I.K., Tran C., Stiles B., Thomas G., Petersen R., Frost P., et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 10314-10319
118. Pacheco-Rodriguez G., Steagall W.K., Crooks D.M., Stevens L.A., Hashimoto H., Li S., et al. TSC2 loss in lymphangioleiomyomatosis cells correlated with expression of CD44v6, a molecular determinant of metastasis. Cancer Res. 67 (2007) 10573-10581
119. Panner A., James C.D., Berger M.S., and Pieper R.O. mTOR controls FLIPS translation and TRAIL sensitivity in glioblastoma multiforme cells. Mol. Cell Biol. 25 (2005) 8809-8823
120. Pende M., Um S.H., Mieulet V., Sticker M., Goss V.L., Mestan J., et al. S6K1(-/-) /S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5'-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol. Cell Biol. 24 (2004) 3112-3124
121. Repasky G.A., Chenette E.J., and Der C.J. Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis?. Trends Cell Biol. 14 (2004) 639-647
122. Roberts P.J., and Der C.J. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26 (2007) 3291-3310
123. Rojo F., Najera L., Lirola J., Jimenez J., Guzman M., Sabadell M.D., et al. 4E-binding protein 1, a cell signaling hallmark in breast cancer that correlates with pathologic grade and prognosis. Clin. Cancer Res. 13 (2007) 81-89
124. Rosenwald I.B., Chen J.J., Wang S., Savas L., London I.M., and Pullman J. Upregulation of protein synthesis initiation factor eIF-4E is an early event during colon carcinogenesis. Oncogene 18 (1999) 2507-2517
125. Rousseau D., Gingras A.C., Pause A., and Sonenberg N. The eIF4E-binding proteins 1 and 2 are negative regulators of cell growth. Oncogene 13 (1996) 2415-2420
126. Roux P.P., Ballif B.A., Anjum R., Gygi S.P., and Blenis J. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl. Acad. Sci. U.S.A. 101 (2004) 13489-13494
127. Rowinsky E.K. Targeting the molecular target of rapamycin (mTOR). Curr. Opin. Oncol. 16 (2004) 564-575
128. 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
129. Salehi Z., and Mashayekhi F. Expression of the eukaryotic translation initiation factor 4E (eIF4E) and 4E-BP1 in esophageal cancer. Clin. Biochem. 39 (2006) 404-409
130. Sampson J.R., and Harris P.C. The molecular genetics of tuberous sclerosis. Hum. Mol. Genet. 3 (1994) 1477-1480
131. 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
132. Schubbert S., Shannon K., and Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat. Rev. Cancer 7 (2007) 295-308
133. Shaw R.J., and Cantley L.C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441 (2006) 424-430
134. Shi Y., Gera J., Hu L., Hsu J.H., Bookstein R., Li W., and Lichtenstein A. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res. 62 (2002) 5027-5034
135. Shuda M., Kondoh N., Tanaka K., Ryo A., Wakatsuki T., Hada A., et al. Enhanced expression of translation factor mRNAs in hepatocellular carcinoma. Anticancer Res. 20 (2000) 2489-2494
136. Skinner H.D., Zheng J.Z., Fang J., Agani F., and Jiang B.H. Vascular endothelial growth factor transcriptional activation is mediated by hypoxia-inducible factor 1alpha, HDM2, and p70S6K1 in response to phosphatidylinositol 3-kinase/AKT signaling. J. Biol. Chem. 279 (2004) 45643-45651
137. Skinner H.D., Zhong X.S., Gao N., Shi X., and Jiang B.H. Arsenite induces p70S6K1 activation and HIF-1alpha expression in prostate cancer cells. Mol. Cell Biochem. 255 (2004) 19-23
138. Small G.W., Shi Y.Y., Higgins L.S., and Orlowski R.Z. Mitogen-activated protein kinase phosphatase-1 is a mediator of breast cancer chemoresistance. Cancer Res. 67 (2007) 4459-4466
139. Sonenberg N., and Gingras A.C. The mRNA 5′ cap-binding protein eIF4E and control of cell growth. Curr. Opin. Cell Biol. 10 (1998) 268-275
140. Sorrells D.L., Black D.R., Meschonat C., Rhoads R., De Benedetti A., Gao M., et al. Detection of eIF4E gene amplification in breast cancer by competitive PCR. Ann. Surg. Oncol. 5 (1998) 232-237
141. Sorrells D.L., Ghali G.E., Meschonat C., DeFatta R.J., Black D., Liu L., et al. Competitive PCR to detect eIF4E gene amplification in head and neck cancer. Head Neck 21 (1999) 60-65
142. Stephan S., Datta K., Wang E., Li J., Brekken R.A., Parangi S., et al. Effect of rapamycin alone and in combination with antiangiogenesis therapy in an orthotopic model of human pancreatic cancer. Clin. Cancer Res. 10 (2004) 6993-7000
143. Stromberg T., Dimberg A., Hammarberg A., Carlson K., Osterborg A., Nilsson K., et al. Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone. Blood 103 (2004) 3138-3147
144. Svensson S., Jirstrom K., Ryden L., Roos G., Emdin S., Ostrowski M.C., and Landberg G. ERK phosphorylation is linked to VEGFR2 expression and Ets-2 phosphorylation in breast cancer and is associated with tamoxifen treatment resistance and small tumours with good prognosis. Oncogene 24 (2005) 4370-4379
145. Tabellini G., Cappellini A., Tazzari P.L., Fala F., Billi A.M., Manzoli L., et al. Phosphoinositide 3-kinase/Akt involvement in arsenic trioxide resistance of human leukemia cells. J. Cell Physiol. 202 (2005) 623-634
146. Tanaka M., and Grossman H.B. In vivo gene therapy of human bladder cancer with PTEN suppresses tumor growth, downregulates phosphorylated Akt, and increases sensitivity to doxorubicin. Gene Ther. 10 (2003) 1636-1642
147. Tazzari P.L., Cappellini A., Ricci F., Evangelisti C., Papa V., Grafone T., et al. Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts. Leukemia 21 (2007) 427-438
148. Thimmaiah K.N., Easton J., Huang S., Veverka K.A., Germain G.S., Harwood F.C., and Houghton P.J. Insulin-like growth factor I-mediated protection from rapamycin-induced apoptosis is independent of Ras-Erk1-Erk2 and phosphatidylinositol 3′-kinase-Akt signaling pathways. Cancer Res. 63 (2003) 364-374
149. Tokunaga E., Kimura Y., Mashino K., Oki E., Kataoka A., Ohno S., et al. Activation of PI3K/Akt signaling and hormone resistance in breast cancer. Breast Cancer 13 (2006) 137-144
150. 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 haematological malignancies. Drug Resist. Update 10 (2007) 81-100
151. Tsang C.K., Qi H., Liu L.F., and Zheng X.F. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov. Today 12 (2007) 112-124
152. Tsurutani J., West K.A., Sayyah J., Gills J.J., and Dennis P.A. Inhibition of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway but not the MEK/ERK pathway attenuates laminin-mediated small cell lung cancer cellular survival and resistance to imatinib mesylate or chemotherapy. Cancer Res. 65 (2005) 8423-8432
153. Vanderweele D.J., and Rudin C.M. Mammalian target of rapamycin promotes vincristine resistance through multiple mechanisms independent of maintained glycolytic rate. Mol. Cancer Res. 3 (2005) 635-644
154. Villedieu M., Deslandes E., Duval M., Heron J.F., Gauduchon P., and Poulain L. Acquisition of chemoresistance following discontinuous exposures to cisplatin is associated in ovarian carcinoma cells with progressive alteration of FAK, ERK and p38 activation in response to treatment. Gynecol. Oncol. 101 (2006) 507-519
155. Wang J., Zhou J.Y., and Wu G.S. ERK-dependent MKP-1-mediated cisplatin resistance in human ovarian cancer cells. Cancer Res. 67 (2007) 11933-11941
156. Wang M.Y., Lu K.V., Zhu S., Dia E.Q., Vivanco I., Shackleford G.M., et al. Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells. Cancer Res. 66 (2006) 7864-7869
157. Wang Z., Xu J., Zhou J.Y., Liu Y., and Wu G.S. Mitogen-activated protein kinase phosphatase-1 is required for cisplatin resistance. Cancer Res. 66 (2006) 8870-8877
158. Ward S.G., and Finan P. Isoform-specific phosphoinositide 3-kinase inhibitors as therapeutic agents. Curr. Opin. Pharmacol. 3 (2003) 426-434
159. White R.J. Regulation of RNA polymerases I and III by the retinoblastoma protein: a mechanism for growth control?. Trends Biochem. Sci. 22 (1997) 77-80
160. Wolthuis R.M., and Bos J.L. Ras caught in another affair: the exchange factors for Ral. Curr. Opin. Genet. Dev. 9 (1999) 112-117
161. Wu C., Wangpaichitr M., Feun L., Kuo M.T., Robles C., Lampidis T., and Savaraj N. Overcoming cisplatin resistance by mTOR inhibitor in lung cancer. Mol. Cancer 4 (2005) 25
162. Yamasaki F., Johansen M.J., Zhang D., et al. Acquired resistance to erlotinib in A-431 epidermoid cancer cells requires down-regulation of MMAC1/PTEN and up-regulation of phosphorylated Akt. Cancer Res. 67 (2007) 5779-5788
163. Yeung R.S., Xiao G.H., Jin F., Lee W.C., Testa J.R., and Knudson A.G. Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. Proc. Natl. Acad. Sci. U.S.A. 91 (1994) 11413-11416
164. Yu Q. Restoring p53-mediated apoptosis in cancer cells: new opportunities for cancer therapy. Drug Resist. Update 9 (2006) 19-25
165. Yu H.G., Ai Y.W., Yu L.L., Zhou X.D., Liu J., Li J.H., et al. Phosphoinositide 3-kinase/Akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death. Int. J. Cancer 122 (2008) 433-443
166. Yuan Z.Q., Feldman R.I., Sussman G.E., Coppola D., Nicosia S.V., and Cheng J.Q. AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by phosphorylation of ASK1: implication of AKT2 in chemoresistance. J. Biol. Chem. 278 (2003) 23432-23440
167. Zhao Y., Shen S., Guo J., Chen H., Greenblatt D.Y., Kleeff J., et al. Mitogen-activated protein kinases and chemoresistance in pancreatic cancer cells. J. Surg. Res. 136 (2006) 325-335
168. Zhong X.S., Zheng J.Z., Reed E., and Jiang B.H. SU5416 inhibited VEGF and HIF-1alpha expression through the PI3K/AKT/p70S6K1 signaling pathway. Biochem. Biophys. Res. Commun. 324 (2004) 471-480
169. Zhou Q., Liu L.Z., Fu B., Hu X., Shi X., Fang J., and Jiang B.H. Reactive oxygen species regulate insulin-induced VEGF and HIF-1alpha expression through the activation of p70S6K1 in human prostate cancer cells. Carcinogenesis 28 (2007) 28-37
170. Zhuang Z.G., Di G.H., Shen Z.Z., Ding J., and Shao Z.M. Enhanced expression of LKB1 in breast cancer cells attenuates angiogenesis, invasion, and metastatic potential. Mol. Cancer Res. 4 (2006) 843-849