Effects and Therapeutic Potential of Targeting Dysregulated Signaling Axes in Squamous Cell Carcinoma: Another Kinase of Transcription and Mammalian Target of Rapamycin

  • Cheryl Clark
  • Oleksandr Ekshyyan
  • Cherie-Ann O. Nathan
Chapter

Abstract

Head and neck squamous cell carcinoma (HNSCC) needs new approaches to treatment, as 500,000 new cases are seen worldwide annually, and recurrences and second primaries result in significant morbidity and poor survival. HNSCC is characterized by a persistent activation of the human v-akt murine thymoma viral oncogene homolog 1 (AKT)/mammalian target of rapamycin (mTOR) pathway that initiates a cascade of cellular events intrinsic to the carcinogenic process including cell survival, proliferation, cell cycle progression, cell growth, transcription and translation, angiogenesis, invasion, and metastasis. The AKT/mTOR pathway integrates a variety of signaling pathways involved in cell growth and division, and inhibitors of this pathway effectively starve the targeted cells.

Keywords

Fatigue Toxicity Paclitaxel Caffeine Cyclosporine 

References

  1. Abraham R, Gibbons J (2007) The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. Clin Cancer Res 13(11):3109–3114PubMedCrossRefGoogle Scholar
  2. Aissat N, Tourneau CL et al. (2008) 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 62(2):305–313PubMedCrossRefGoogle Scholar
  3. Alessi D, Andjelkovic M et al. (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15(23):6541–6551PubMedGoogle Scholar
  4. Alessi D, James S et al. (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7(4):261–269PubMedCrossRefGoogle Scholar
  5. Amato R, Jac J et al. (2009) A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer. Cancer 115(11):2438–2446PubMedCrossRefGoogle Scholar
  6. Amornphimoltham P, Sriuranpong V et al. (2004) Persistent activation of the Akt pathway in head and neck squamous cell carcinoma: a potential target for UCN-01. Clin Cancer Res 10(12 Pt 1):4029–4037PubMedCrossRefGoogle Scholar
  7. Amornphimoltham P, Patel V et al. (2005) Mammalian target of rapamycin, a molecular target in squamous cell carcinomas of the head and neck. Cancer Res 65(21):9953–9961PubMedCrossRefGoogle Scholar
  8. Amornphimoltham P, Patel V et al. (2008) A retroinhibition approach reveals a tumor cell-autonomous response to rapamycin in head and neck cancer. Cancer Res 68(4):1144–1153PubMedCrossRefGoogle Scholar
  9. Argiris A, Cohen E et al. (2006) A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer. Cancer Biol Ther 5(7):766–770PubMedGoogle Scholar
  10. Astsaturov I, Cohen R et al. (2006) EGFR-targeting monoclonal antibodies in head and neck ­cancer. Curr Cancer Drug Targets 6(8):697–710CrossRefGoogle Scholar
  11. Ballou L, Lin R (2008) Rapamycin and mTOR kinase inhibit. J Chem Biol 1(1–4):27–36PubMedCrossRefGoogle Scholar
  12. Baselga J, Arteaga C (2005) Critical update and emerging trends in epidermal growth factor ­receptor targeting in can. J Clin Oncol 23(11):2445–2459PubMedCrossRefGoogle Scholar
  13. Beeram M, Tan Q et al. (2007) Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling. Ann Oncol 18(8):1323–1328PubMedCrossRefGoogle Scholar
  14. Bianco F, Garofalo S et al. (2008) Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs. Br J Cancer 98(5):923–930PubMedCrossRefGoogle Scholar
  15. Bianco R, Shin I et al. (2003) Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 22(18):2812–2822PubMedCrossRefGoogle Scholar
  16. Birle D, Hedley D (2006) Signaling interactions of rapamycin combined with erlotinib in cervical carcinoma xenografts. Mol Cancer Ther 5(10):2494–2502PubMedCrossRefGoogle Scholar
  17. Brazil D, Hemmings B (2001) Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 26(11):657–664PubMedCrossRefGoogle Scholar
  18. Brown R, Zhang P et al. (2006) Morphoproteomic and pharmacoproteomic rationale for mTOR effectors as therapeutic targets in head and neck squamous cell carcinoma. Ann Clin Lab Sci 36(3):273–282PubMedGoogle Scholar
  19. Buck E, Eyzaguirre A et al. (2006) Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol Cancer Ther 5(11):2676–2684PubMedCrossRefGoogle Scholar
  20. Budach W, Bölke E et al. (2007) Severe cutaneous reaction during radiation therapy with concurrent cetuximab. N Engl J Med 357(5):514–515PubMedCrossRefGoogle Scholar
  21. Cantley L, Neel B (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 96(8):4240–4245PubMedCrossRefGoogle Scholar
  22. Carracedo A, Pandolfi P (2008) The PTEN-PI3K pathway of feedbacks and cross-talks. Oncogene 27(41):5527–5541PubMedCrossRefGoogle Scholar
  23. Cejka D, Preusser M et al. (2008) mTOR inhibition sensitizes gastric cancer to alkylating chemotherapy in vivo. Antican Res 28(6A):3801–3808Google Scholar
  24. Chakravati A, Loeffler J et al. (2002) Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res 62(1):200–207Google Scholar
  25. Chan F, Samlowski E et al. (2009) Temsirolimus: a review of its use in the treatment of advanced renal cell carcinoma. Clin Med Therapeut 1:167–174Google Scholar
  26. Cloughesy T, Yoshimoto K et al. (2008) Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 5(1):e8PubMedCrossRefGoogle Scholar
  27. Cohen E, Kane M et al. (2005) Phase II trial of Gefitinib 250 mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 11(23):8418–8424PubMedCrossRefGoogle Scholar
  28. Cooper J, Cohen E (2009) Mechanisms of resistance to EGFR inhibitors in head and neck cancer. Head Neck 31(8):1086–1094, doi:10.1002/hed.21109PubMedCrossRefGoogle Scholar
  29. Cully M, You H et al. (2006) Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 6(3):184–192PubMedCrossRefGoogle Scholar
  30. Czerninski R, Amornphimoltham P et al. (2009) Targeting mammalian target of rapamycin by rapamycin prevents tumor progression in an oral-specific chemical carcinogenesis model. Cancer Prev Res 2(1):27–36CrossRefGoogle Scholar
  31. Dancey J (2002) Clinical development of mammalian target of rapamycin inhibitors. Hematol Oncol Clin North Am 16(5):1101–1114PubMedCrossRefGoogle Scholar
  32. Dancey J (2005) Inhibitors of the mammalian target of rapamycin. Expert Opin Investig Drugs 14(3):313–328PubMedCrossRefGoogle Scholar
  33. Dasqupta P, Rizwani W et al. (2009) Nicotine induces cell proliferation, invasion and epithelial-mesenchymal transition in a variety of human cancer cell lines. Int J Cancer 124(1):36–45CrossRefGoogle Scholar
  34. DeBenedetti A, Joshi B et al. (1994) CHO cells transformed by the translation factor eIF4E display increased c-Myc expression but require overexpression of Max for tumorigenicity. Mol Cell Diff 2:347–371Google Scholar
  35. DeBenedetti A, Harris A (1999) eIF4E expression in tumors: its possible role in progression of malignancies. Int J Biochem Cell Biol 31(1):59–72CrossRefGoogle Scholar
  36. DeGraffenried L, Friedrichs W et al. (2004) Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res 10(23):8059–8067PubMedCrossRefGoogle Scholar
  37. DelBufalo D, Ciuffreda L et al. (2006) Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 66(11):5549–5554CrossRefGoogle Scholar
  38. Dennis P (2009) Rapamycin for chemoprevention of upper aerodigestive tract cancers. Cancer Prev Res 2(1):7–9CrossRefGoogle Scholar
  39. Dobashi Y, Suzuki S et al. (2009) Critical and diverse involvement of Akt/mammalian target of rapamycin signaling in human lung carcinomas. Cancer 115(1):107–118PubMedCrossRefGoogle Scholar
  40. Dufner A, Thomas G (1999) Ribosomal S6 kinase signaling and the control of translation. Exp Cell Res 253(1):100–109PubMedCrossRefGoogle Scholar
  41. Ekshyyan O, Rong Y et al. (2009) Comparison of radiosensitizing effects of the mTOR inhibitor CCI-779 to cisplatin in experimental models of head and neck squamous cell carcinoma. Mol Cancer Ther 8(8):2255–2265PubMedCrossRefGoogle Scholar
  42. Engelman J, Luo J et al. (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7(8):606–619PubMedCrossRefGoogle Scholar
  43. Faivre S, Kroemer G et al. (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5(8):671–688PubMedCrossRefGoogle Scholar
  44. Feng W, Duan X et al. (2009) Morphoproteomic evidence of constitutively activated and over­expressed mTOR pathway in cervical squamous carcinoma and high grade squamous intra­epithelial lesions. Int J Clin Exp Pathol 2(3):249–260PubMedGoogle Scholar
  45. Feun L, Savaraj N et al. (1984) Phase I study of tricyclic nucleoside phosphate using a five-day continuous infusion schedule. Cancer Res 44(8):3608–3612PubMedGoogle Scholar
  46. Feun L, Blessing J et al. (1993) A phase II trial of tricyclic nucleoside phosphate in patients with advanced squamous cell carcinoma of the cervix. A Gynecologic Oncology Group study. Am J Clin Oncol 16(6):506–508PubMedCrossRefGoogle Scholar
  47. Figlin R, Brown E et al. (2008) NCCN Task Force Report: mTOR inhibition in solid tumors. J Natl Compr Canc Netw 6(Suppl 5):S1–S20PubMedGoogle Scholar
  48. Flynn A, Proud C (1996) The role of eIF4 in cell proliferation. Cancer Surv 27:293–310PubMedGoogle Scholar
  49. Forastiere A, Koch W et al. (2001) Head and neck cancer. N Engl J Med 345(26):1890–1900PubMedCrossRefGoogle Scholar
  50. Gadducci A, Tana R et al. (2008) Molecular target therapies in endometrial cancer: from the basic research to the clinic. Gynecol Endocrinol 24(5):239–249PubMedCrossRefGoogle Scholar
  51. Gold K, Lee H et al. (2009) Targeted therapies in squamous cell carcinoma of the head and neck. Cancer 115(5):922–935PubMedCrossRefGoogle Scholar
  52. Guertin D, Stevens D et al. (2006) 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(6):859–871PubMedCrossRefGoogle Scholar
  53. Gusterson B, Hunter K (2009) Should we be surprised at the paucity of response to EGFR inhibitors? Lancet Oncol 10(5):522–527PubMedCrossRefGoogle Scholar
  54. Hanrahan E, Kies M et al. (2009) A phase II study of Lonafarnib (SCH66336) in patients with chemorefractory, advanced squamous cell carcinoma of the head and neck. Am J Clin Oncol 32(3):274–279, doi:10.1097/COC.0b013e318187dd57PubMedCrossRefGoogle Scholar
  55. Hashimoto I, Koizumi K et al. (2008) Blocking on the CXCR4/mTOR signalling pathway induces the anti-metastatic properties and autophagic cell death in peritoneal disseminated gastric cancer cells. Eur J Cancer 44(7):1022–1029PubMedCrossRefGoogle Scholar
  56. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18(16):1926–1945PubMedCrossRefGoogle Scholar
  57. Helliwell S, Wagner P et al. (1994) TOR1 and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast. Mol Biol Cell 5(1):105–118PubMedGoogle Scholar
  58. Hidalgo M, Buckner J et al. (2006) A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 12(19):5755–5763PubMedCrossRefGoogle Scholar
  59. Hou G, Xue L et al. (2007) An activated mTOR/p70S6K signaling pathway in esophageal squamous cell carcinoma cell lines and inhibition of the pathway by rapamycin and siRNA against mTOR. Cancer Lett 253(2):236–248PubMedCrossRefGoogle Scholar
  60. Huang S, Houghton P (2002) Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr Opin Investig Drugs 3(2):295–304PubMedGoogle Scholar
  61. Hudes G, Carducci M et al. (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356(22):2271–2281PubMedCrossRefGoogle Scholar
  62. Janmaat M, Kruyt F et al. (2003) Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. Clin Cancer Res 9(6):2316–2326PubMedGoogle Scholar
  63. Jimeno A, Kulesza P et al. (2007) Dual EGFR and mTOR targeting in squamous cell carcinoma models, and development of early markers of efficacy. Br J Cancer 96(6):952–959PubMedCrossRefGoogle Scholar
  64. Kandel E, Hay N (1999) The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res 253(1):210–229PubMedCrossRefGoogle Scholar
  65. Khariwala S, Kjaergaard J et al. (2006) Everolimus (RAD) inhibits in vivo growth of murine squamous cell carcinoma (SCC VII). Laryngoscope 116(5):814–820PubMedCrossRefGoogle Scholar
  66. Kondapaka S, Singh S et al. (2003) Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2(11):1093–1103PubMedGoogle Scholar
  67. Kopelovich L, Fay J et al. (2007) The mammalian target of rapamycin pathway as a potential target for cancer chemoprevention. Cancer Epidemiol Biomarkers Prev 16(7):1330–1340PubMedCrossRefGoogle Scholar
  68. Kunz J, Henriquez R et al. (1993) Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73(3):585–596PubMedCrossRefGoogle Scholar
  69. Lacouture M (2006) Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 6(10):803–812PubMedCrossRefGoogle Scholar
  70. LaMonica S, Galetti M et al. (2009) Everolimus restores Gefitinib sensitivity in resistant non-small cell lung cancer cell lines. Biochem Pharmacol 78(5):460–468, doi:10.1016/j.bcp.2009.04.033CrossRefGoogle Scholar
  71. Lane H, Wood J et al. (2009) mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin Cancer Res 15(5):1612–1622PubMedCrossRefGoogle Scholar
  72. Laurent-Puig P, Lievre A et al. (2009) Mutations and response to epidermal growth factor receptor inhibitors. Clin Cancer Res 15(4):1133–1139PubMedCrossRefGoogle Scholar
  73. Lin J, Adam R et al. (1999) The phosphatidylinositol 3’-kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells. Cancer Res 59(12):2891–2897PubMedGoogle Scholar
  74. Lippman S, Heymach J (2007) The convergent development of molecular-targeted drugs for cancer treatment and prevention. Clin Cancer Res 13(14):4035–4041PubMedCrossRefGoogle Scholar
  75. Lord H, Junor E et al. (2008) Cetuximab is effective, but more toxic than reported in the Bonner trial. Clin Oncol 20(1):96CrossRefGoogle Scholar
  76. Mahalingam D, Sankhala K et al. (2009) Targeting the mTOR pathway using deforolimus in ­cancer therapy. Future Oncol 5(3):291–303PubMedCrossRefGoogle Scholar
  77. Maher E, Furnari F et al. (2001) Malignant glioma: genetics and biology of a grave matter. Genes Dev 15(11):1311–1333PubMedCrossRefGoogle Scholar
  78. Mao L, Hong W et al (2004) Focus on head and neck cancer. Cancer Cell 5(4):311–316PubMedCrossRefGoogle Scholar
  79. Marone R, Erhart D et al. (2009) Targeting melanoma with dual phosphoinositide 3-kinase/­mammalian target of rapamycin inhibitors. Mol Cancer Res 7(4):601–613PubMedCrossRefGoogle Scholar
  80. Mehanna H, Rattay T et al. (2009) Treatment and follow-up of oral dysplasia – A systematic review and meta-analysis. Head Neck 31(12):1600–1609, doi:10.1002/hed.21131PubMedCrossRefGoogle Scholar
  81. Meier F, Busch S et al. (2007) Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment. Br J Dermatol 156(6):1204–1213PubMedCrossRefGoogle Scholar
  82. Meric-Bernstam F, Gonzalez-Angulo A (2009) Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 27(13):2278–2287PubMedCrossRefGoogle Scholar
  83. Molina J, Mandrekar S et al. (2007) A phase II NCCTG “Window of Opportunity Front-line” study of the mTOR inhibitor, CCI-779 (temsirolimus) given as a single agent in patients with advanced NSCLC [abstract]. J Thorac Oncol 2(suppl 4):S413CrossRefGoogle Scholar
  84. Molinolo A, Hewitt S et al. (2007) Dissecting the Akt/mammalian target of rapamycin signaling network: emerging results from the head and neck cancer tissue array initiative. Clin Cancer Res 13(17):4964–4973PubMedCrossRefGoogle Scholar
  85. Moral M, Segrelles C et al. (2009) Akt activation synergizes with Trp53 loss in oral epithelium to produce a novel mouse model for head and neck squamous cell carcinoma. Cancer Res 69(3):1099–1108PubMedCrossRefGoogle Scholar
  86. Morath C, Arns W et al. (2007) Sirolimus in renal transplantation. Nephrol Dial Transplant 22(Suppl 8):viii61–viii65PubMedCrossRefGoogle Scholar
  87. Motzer R, Escudier B et al. (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372(9637):449–456PubMedCrossRefGoogle Scholar
  88. Nakayama H, Ikebe T et al. (2001) High expression levels of nuclear factor kappaB, IkappaB kinase alpha and Akt kinase in squamous cell carcinoma of the oral cavity. Cancer 92(12):3037–3044PubMedCrossRefGoogle Scholar
  89. Nathan C, Franklin S et al. (1999) Analysis of surgical margins with the molecular marker eIF4E: a prognostic factor in patients with head and neck cancer. J Clin Oncol 17(9):2909–2914PubMedGoogle Scholar
  90. Nathan C, Amirghahari N et al. (2002) Molecular analysis of surgical margins in head and neck squamous cell carcinoma patients. Laryngoscope 112(12):2129–2140PubMedCrossRefGoogle Scholar
  91. Nathan C, Amirghahari N et al. (2004) Overexpressed eIF4E is functionally active in surgical margins of head and neck cancer patients via activation of the Akt/mammalian target of rapamycin pathway. Clin Cancer Res 10(17):5820–5827PubMedCrossRefGoogle Scholar
  92. Nathan C, Amirghahari N et al. (2007a) Mammalian target of rapamycin inhibitors as possible adjuvant therapy for microscopic residual disease in head and neck squamous cell cancer. Cancer Res 67(5):2160–2168PubMedCrossRefGoogle Scholar
  93. Nathan C, Mills G et al. (2007b) An exploratory biomarker trial of an mTOR inhibitor in subjects with newly diagnosed advanced stage HNSCC. Proc AACR Suppl 48:42Google Scholar
  94. O’Donnell A, Faivre S et al. (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 26(10):1588–1595PubMedCrossRefGoogle Scholar
  95. O’Reilly K, Rojo F et al. (2006) mTOR inhibition induces upstream receptor tyrosine kinase ­signaling and activates Akt. Cancer Res 66(3):1500–1508PubMedCrossRefGoogle Scholar
  96. Oh S, Jin Q et al. (2008) Insulin-like growth factor-I receptor signaling pathway induces resistance to the apoptotic activities of SCH66336 (lonafarnib) through Akt/mammalian target of rapamycin-mediated increases in survivin expression. Clin Cancer Res 14(5):1581–1589PubMedCrossRefGoogle Scholar
  97. Okuno S (2006) Mammalian target of rapamycin inhibitors in sarcomas. Curr Opin Oncol 18(4):360–362PubMedCrossRefGoogle Scholar
  98. Papadimitrakopoulou V, Soria J et al. (2007) A phase II study of RAD001 (r) (everolimus) ­monotherapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) failing prior platinum-based chemotherapy (c) or prior c and EGFR inhibitors (EGFR-I) [abstract]. J Clin Oncol 25(18 suppl):406sGoogle Scholar
  99. Patel V, Lahusen T et al. (2002) Perifosine, a novel alkylphospholipid, induces p21(WAF1) expression in squamous carcinoma cells through a p53-independent pathway, leading to loss in cyclin-dependent kinase activity and cell cycle arrest. Cancer Res 62(5):1401–1409PubMedGoogle Scholar
  100. Phan A, Yao J (2008) Neuroendocrine tumors: novel approaches in the age of targeted therapy. Oncology 22(14):1617–1623PubMedGoogle Scholar
  101. Phung T, Ziv K et al. (2006) Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 10(2):159–170PubMedCrossRefGoogle Scholar
  102. Pullen N, Thomas G (1997) The modular phosphorylation and activation of p70s6k. FEBS Lett 410(1):78–82PubMedCrossRefGoogle Scholar
  103. Raimondi A, Molinolo A et al. (2009) Rapamycin prevents early onset of tumorigenesis in an oral-specific K-ras and p53 two-hit carcinogenesis model. Cancer Res 69(10):4159–4166PubMedCrossRefGoogle Scholar
  104. Rao R, Buckner J et al. (2004) Mammalian target of rapamycin (mTOR) inhibitors as anti-cancer agents. Curr Cancer Drug Targets 4(8):621–635PubMedCrossRefGoogle Scholar
  105. Raymond E, Alexandre J et al. (2004) Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 22(12):2336–2347PubMedCrossRefGoogle Scholar
  106. Reibel J (2003) Prognosis of oral pre-malignant lesions: significance of clinical, histopathological, and molecular biological characteristics. Crit Rev Oral Biol Med 14(1):47–62PubMedCrossRefGoogle Scholar
  107. Rexer B, Engelman J et al. (2009) Overcoming resistance to tyrosine kinase inhibitors: lessons learned from cancer cells treated with EGFR antagonists. Cell Cycle 8(1):18–22PubMedGoogle Scholar
  108. Rhoads R (1993) Regulation of eukaryotic protein synthesis by initiation factors. J Biol Chem 268(5):3017–3020PubMedGoogle Scholar
  109. Rojo F, Tabernero J et al. (2006) Pharmacodynamic studies of gefitinib in tumor biopsy specimens from patients with advanced gastric carcinoma. J Clin Oncol 24(26):4309–4316PubMedCrossRefGoogle Scholar
  110. Rosenwald I, Kaspar R et al. (1995) Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. J Biol Chem 270:21176–21180PubMedCrossRefGoogle Scholar
  111. Rowinsky E (2004) Targeting the molecular target of rapamycin (mTOR). Curr Opin Oncol 16(6):564–575PubMedCrossRefGoogle Scholar
  112. Sankhala K, Mita A et al. (2009) The emerging safety profile of mTOR inhibitors, a novel class of anticancer agents. Target Oncol 4(2):135–142, doi:10.1007/s11523-009-0107-zPubMedCrossRefGoogle Scholar
  113. Sarbassov D, Ali S et al. (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14(14):1296–1302PubMedCrossRefGoogle Scholar
  114. Sarbassov D, Guertin D et al. (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101PubMedCrossRefGoogle Scholar
  115. Sarbassov D, Ali S et al. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159–168PubMedCrossRefGoogle Scholar
  116. Scheid M, Woodgett J (2001) PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2(10):760–768PubMedCrossRefGoogle Scholar
  117. Sehgal S, Baker H et al. (1975) Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo) 28(10):727–732Google Scholar
  118. Shantz L, Pegg A (1994) Overproduction of ornithine decarboxylase caused by relief of translational repression is associated with neoplastic transformation. Cancer Res 54:2313–2316PubMedGoogle Scholar
  119. Shinohara E, Maity A et al. (2009) Sirolimus as a potential radiosensitizer in squamous cell cancer of the head and neck. Head Neck 31(3):406–411PubMedCrossRefGoogle Scholar
  120. Sok J, Coppelli F et al. (2006) Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res 12(17):5064–5073PubMedCrossRefGoogle Scholar
  121. Soulieres D, Senzer N et al. (2004) Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol 22(1):77–85PubMedCrossRefGoogle Scholar
  122. Sun S, Rosenberg L et al. (2005) Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 65(16):7052–7058PubMedCrossRefGoogle Scholar
  123. Thariat J, Yildirim G et al. (2007) Combination of radiotherapy with EGFR antagonists for head and neck carcinoma. Int J Clin Oncol 12(2):99–110PubMedCrossRefGoogle Scholar
  124. Tsurutani J, Castillo S et al. (2005) Tobacco components stimulate Akt-dependent proliferation and NFkappaB-dependent survival in lung cancer cells. Carcinogenesis 26(7):1182–1195PubMedCrossRefGoogle Scholar
  125. Vignot S, Faivre S et al. (2005) mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 16(4):525–537PubMedCrossRefGoogle Scholar
  126. Vink S, Lagerwerf S et al. (2006) Radiosensitization of squamous cell carcinoma by the alkylphospholipid perifosine in cell culture and xenografts. Clin Cancer Res 12(5):1615–1622PubMedCrossRefGoogle Scholar
  127. Vivanco I, Sawyers CL (2002) The phosphatidylinositol pathway in human cancer. Nat Rev Cancer 2(7):489–501PubMedCrossRefGoogle Scholar
  128. Wan X, Harkavy B et al. (2007) Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26(13):1932–1940PubMedCrossRefGoogle Scholar
  129. Wang L, Ignat A et al. (2002) Differential expression of the PTEN tumor suppressor protein in fetal and adult neuroendocrine tissues and tumors: progressive loss of PTEN expression in poorly ­differentiated neuroendocrine neoplasms. Appl Immunohistochem Mol Morphol 10(2):139–146PubMedCrossRefGoogle Scholar
  130. Wang X, McCullough K et al. (2000) Epidermal growth factor receptor-dependent Akt activation by oxidative stress enhances cell survival. J Biol Chem 275(19):14624–14631PubMedCrossRefGoogle Scholar
  131. Wang X, Li W et al. (2001) Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J 20(16):4370–4379PubMedCrossRefGoogle Scholar
  132. Wee S, Jagani Z et al. (2009) PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res 69(10):OF1–OF8CrossRefGoogle Scholar
  133. Wen Y, Hu M et al. (2000) HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res 60(24):6841–6845PubMedGoogle Scholar
  134. Wendel H, DeStanchina E et al. (2004) Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428(6980):332–337PubMedCrossRefGoogle Scholar
  135. Wullschleger S, Loewith R et al. (2006) TOR signaling in growth and metabolism. Cell 124(3):471–484PubMedCrossRefGoogle Scholar
  136. Yang L, Dan H et al. (2004) Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res 64(13):4394–4399PubMedCrossRefGoogle Scholar
  137. Yoshioka A, Miyata H et al. (2008) The activation of Akt during preoperative chemotherapy for esophageal cancer correlates with poor prog. Oncol Rep 19(5):1099–1107PubMedGoogle Scholar
  138. Yu K, Toral-Barza L et al. (2001) mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer 8:249–258PubMedCrossRefGoogle Scholar
  139. Yun H, Bogaerts J et al. (2007) Clinical trial design limitations in head and neck squamous cell carcinomas. Curr Opin Oncol 19(3):210–215PubMedCrossRefGoogle Scholar
  140. Zeng Z, Sarbassov D et al. (2007) Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109(8):3509–3512PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Cheryl Clark
  • Oleksandr Ekshyyan
  • Cherie-Ann O. Nathan
    • 1
    • 2
  1. 1.Department of Otolaryngology-Head and Neck SurgeryLouisiana State University Health Sciences CenterShreveportUSA
  2. 2.Feist-Weiller Cancer CenterShreveportUSA

Personalised recommendations