Skip to main content
SpringerLink
Log in

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

  • Chapter
  • First Online:
Book cover Signaling Pathways in Squamous Cancer

  • 580 Accesses

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • 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):3109–3114

    Article  PubMed  CAS  Google Scholar 

  • 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):305–313

    Article  PubMed  CAS  Google Scholar 

  • Alessi D, Andjelkovic M et al. (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15(23):6541–6551

    PubMed  CAS  Google Scholar 

  • 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):261–269

    Article  PubMed  CAS  Google Scholar 

  • 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):2438–2446

    Article  PubMed  CAS  Google Scholar 

  • 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):4029–4037

    Article  PubMed  CAS  Google Scholar 

  • 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):9953–9961

    Article  PubMed  CAS  Google Scholar 

  • 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):1144–1153

    Article  PubMed  CAS  Google Scholar 

  • 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):766–770

    PubMed  CAS  Google Scholar 

  • Astsaturov I, Cohen R et al. (2006) EGFR-targeting monoclonal antibodies in head and neck ­cancer. Curr Cancer Drug Targets 6(8):697–710

    Article  Google Scholar 

  • Ballou L, Lin R (2008) Rapamycin and mTOR kinase inhibit. J Chem Biol 1(1–4):27–36

    Article  PubMed  Google Scholar 

  • Baselga J, Arteaga C (2005) Critical update and emerging trends in epidermal growth factor ­receptor targeting in can. J Clin Oncol 23(11):2445–2459

    Article  PubMed  CAS  Google Scholar 

  • Beeram M, Tan Q et al. (2007) Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling. Ann Oncol 18(8):1323–1328

    Article  PubMed  CAS  Google Scholar 

  • 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):923–930

    Article  PubMed  CAS  Google Scholar 

  • 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):2812–2822

    Article  PubMed  CAS  Google Scholar 

  • Birle D, Hedley D (2006) Signaling interactions of rapamycin combined with erlotinib in cervical carcinoma xenografts. Mol Cancer Ther 5(10):2494–2502

    Article  PubMed  CAS  Google Scholar 

  • Brazil D, Hemmings B (2001) Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 26(11):657–664

    Article  PubMed  CAS  Google Scholar 

  • 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):273–282

    PubMed  CAS  Google Scholar 

  • 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):2676–2684

    Article  PubMed  CAS  Google Scholar 

  • Budach W, Bölke E et al. (2007) Severe cutaneous reaction during radiation therapy with concurrent cetuximab. N Engl J Med 357(5):514–515

    Article  PubMed  CAS  Google Scholar 

  • 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):4240–4245

    Article  PubMed  CAS  Google Scholar 

  • Carracedo A, Pandolfi P (2008) The PTEN-PI3K pathway of feedbacks and cross-talks. Oncogene 27(41):5527–5541

    Article  PubMed  CAS  Google Scholar 

  • Cejka D, Preusser M et al. (2008) mTOR inhibition sensitizes gastric cancer to alkylating chemotherapy in vivo. Antican Res 28(6A):3801–3808

    CAS  Google Scholar 

  • 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):200–207

    Google Scholar 

  • Chan F, Samlowski E et al. (2009) Temsirolimus: a review of its use in the treatment of advanced renal cell carcinoma. Clin Med Therapeut 1:167–174

    CAS  Google Scholar 

  • 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):e8

    Article  PubMed  CAS  Google Scholar 

  • 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):8418–8424

    Article  PubMed  CAS  Google Scholar 

  • 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.21109

    Article  PubMed  Google Scholar 

  • 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):184–192

    Article  PubMed  CAS  Google Scholar 

  • 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):27–36

    Article  CAS  Google Scholar 

  • Dancey J (2002) Clinical development of mammalian target of rapamycin inhibitors. Hematol Oncol Clin North Am 16(5):1101–1114

    Article  PubMed  Google Scholar 

  • Dancey J (2005) Inhibitors of the mammalian target of rapamycin. Expert Opin Investig Drugs 14(3):313–328

    Article  PubMed  CAS  Google Scholar 

  • 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):36–45

    Article  CAS  Google Scholar 

  • 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 2:347–371

    CAS  Google Scholar 

  • DeBenedetti A, Harris A (1999) eIF4E expression in tumors: its possible role in progression of malignancies. Int J Biochem Cell Biol 31(1):59–72

    Article  CAS  Google Scholar 

  • 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):8059–8067

    Article  PubMed  CAS  Google Scholar 

  • DelBufalo D, Ciuffreda L et al. (2006) Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 66(11):5549–5554

    Article  CAS  Google Scholar 

  • Dennis P (2009) Rapamycin for chemoprevention of upper aerodigestive tract cancers. Cancer Prev Res 2(1):7–9

    Article  CAS  Google Scholar 

  • 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):107–118

    Article  PubMed  CAS  Google Scholar 

  • Dufner A, Thomas G (1999) Ribosomal S6 kinase signaling and the control of translation. Exp Cell Res 253(1):100–109

    Article  PubMed  CAS  Google Scholar 

  • 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):2255–2265

    Article  PubMed  CAS  Google Scholar 

  • Engelman J, Luo J et al. (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7(8):606–619

    Article  PubMed  CAS  Google Scholar 

  • Faivre S, Kroemer G et al. (2006) Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5(8):671–688

    Article  PubMed  CAS  Google Scholar 

  • 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):249–260

    PubMed  CAS  Google Scholar 

  • 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):3608–3612

    PubMed  CAS  Google Scholar 

  • 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):506–508

    Article  PubMed  CAS  Google Scholar 

  • 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–S20

    PubMed  CAS  Google Scholar 

  • Flynn A, Proud C (1996) The role of eIF4 in cell proliferation. Cancer Surv 27:293–310

    PubMed  CAS  Google Scholar 

  • Forastiere A, Koch W et al. (2001) Head and neck cancer. N Engl J Med 345(26):1890–1900

    Article  PubMed  CAS  Google Scholar 

  • Gadducci A, Tana R et al. (2008) Molecular target therapies in endometrial cancer: from the basic research to the clinic. Gynecol Endocrinol 24(5):239–249

    Article  PubMed  CAS  Google Scholar 

  • Gold K, Lee H et al. (2009) Targeted therapies in squamous cell carcinoma of the head and neck. Cancer 115(5):922–935

    Article  PubMed  CAS  Google Scholar 

  • 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):859–871

    Article  PubMed  CAS  Google Scholar 

  • Gusterson B, Hunter K (2009) Should we be surprised at the paucity of response to EGFR inhibitors? Lancet Oncol 10(5):522–527

    Article  PubMed  CAS  Google Scholar 

  • 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.0b013e318187dd57

    Article  PubMed  CAS  Google Scholar 

  • 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):1022–1029

    Article  PubMed  CAS  Google Scholar 

  • Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18(16):1926–1945

    Article  PubMed  CAS  Google Scholar 

  • 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):105–118

    PubMed  CAS  Google Scholar 

  • 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):5755–5763

    Article  PubMed  CAS  Google Scholar 

  • 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):236–248

    Article  PubMed  CAS  Google Scholar 

  • 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):295–304

    PubMed  CAS  Google Scholar 

  • Hudes G, Carducci M et al. (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356(22):2271–2281

    Article  PubMed  CAS  Google Scholar 

  • 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):2316–2326

    PubMed  CAS  Google Scholar 

  • 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):952–959

    Article  PubMed  CAS  Google Scholar 

  • Kandel E, Hay N (1999) The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res 253(1):210–229

    Article  PubMed  CAS  Google Scholar 

  • Khariwala S, Kjaergaard J et al. (2006) Everolimus (RAD) inhibits in vivo growth of murine squamous cell carcinoma (SCC VII). Laryngoscope 116(5):814–820

    Article  PubMed  Google Scholar 

  • Kondapaka S, Singh S et al. (2003) Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2(11):1093–1103

    PubMed  CAS  Google Scholar 

  • 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):1330–1340

    Article  PubMed  CAS  Google Scholar 

  • 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):585–596

    Article  PubMed  CAS  Google Scholar 

  • Lacouture M (2006) Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 6(10):803–812

    Article  PubMed  CAS  Google Scholar 

  • 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.2009.04.033

    Article  CAS  Google Scholar 

  • 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):1612–1622

    Article  PubMed  CAS  Google Scholar 

  • Laurent-Puig P, Lievre A et al. (2009) Mutations and response to epidermal growth factor receptor inhibitors. Clin Cancer Res 15(4):1133–1139

    Article  PubMed  CAS  Google Scholar 

  • 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):2891–2897

    PubMed  CAS  Google Scholar 

  • Lippman S, Heymach J (2007) The convergent development of molecular-targeted drugs for cancer treatment and prevention. Clin Cancer Res 13(14):4035–4041

    Article  PubMed  CAS  Google Scholar 

  • Lord H, Junor E et al. (2008) Cetuximab is effective, but more toxic than reported in the Bonner trial. Clin Oncol 20(1):96

    Article  CAS  Google Scholar 

  • Mahalingam D, Sankhala K et al. (2009) Targeting the mTOR pathway using deforolimus in ­cancer therapy. Future Oncol 5(3):291–303

    Article  PubMed  CAS  Google Scholar 

  • Maher E, Furnari F et al. (2001) Malignant glioma: genetics and biology of a grave matter. Genes Dev 15(11):1311–1333

    Article  PubMed  CAS  Google Scholar 

  • Mao L, Hong W et al (2004) Focus on head and neck cancer. Cancer Cell 5(4):311–316

    Article  PubMed  CAS  Google Scholar 

  • Marone R, Erhart D et al. (2009) Targeting melanoma with dual phosphoinositide 3-kinase/­mammalian target of rapamycin inhibitors. Mol Cancer Res 7(4):601–613

    Article  PubMed  CAS  Google Scholar 

  • 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.21131

    Article  PubMed  Google Scholar 

  • 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):1204–1213

    Article  PubMed  CAS  Google Scholar 

  • Meric-Bernstam F, Gonzalez-Angulo A (2009) Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 27(13):2278–2287

    Article  PubMed  CAS  Google Scholar 

  • 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):S413

    Article  Google Scholar 

  • 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):4964–4973

    Article  PubMed  CAS  Google Scholar 

  • 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):1099–1108

    Article  PubMed  CAS  Google Scholar 

  • Morath C, Arns W et al. (2007) Sirolimus in renal transplantation. Nephrol Dial Transplant 22(Suppl 8):viii61–viii65

    Article  PubMed  CAS  Google Scholar 

  • 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):449–456

    Article  PubMed  CAS  Google Scholar 

  • 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):3037–3044

    Article  PubMed  CAS  Google Scholar 

  • 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):2909–2914

    PubMed  CAS  Google Scholar 

  • Nathan C, Amirghahari N et al. (2002) Molecular analysis of surgical margins in head and neck squamous cell carcinoma patients. Laryngoscope 112(12):2129–2140

    Article  PubMed  CAS  Google Scholar 

  • 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):5820–5827

    Article  PubMed  CAS  Google Scholar 

  • 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):2160–2168

    Article  PubMed  CAS  Google Scholar 

  • 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 48:42

    Google Scholar 

  • 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):1588–1595

    Article  PubMed  CAS  Google Scholar 

  • O’Reilly K, Rojo F et al. (2006) mTOR inhibition induces upstream receptor tyrosine kinase ­signaling and activates Akt. Cancer Res 66(3):1500–1508

    Article  PubMed  CAS  Google Scholar 

  • 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):1581–1589

    Article  PubMed  CAS  Google Scholar 

  • Okuno S (2006) Mammalian target of rapamycin inhibitors in sarcomas. Curr Opin Oncol 18(4):360–362

    Article  PubMed  CAS  Google Scholar 

  • 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):406s

    Google Scholar 

  • 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):1401–1409

    PubMed  CAS  Google Scholar 

  • Phan A, Yao J (2008) Neuroendocrine tumors: novel approaches in the age of targeted therapy. Oncology 22(14):1617–1623

    PubMed  Google Scholar 

  • Phung T, Ziv K et al. (2006) Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 10(2):159–170

    Article  PubMed  CAS  Google Scholar 

  • Pullen N, Thomas G (1997) The modular phosphorylation and activation of p70s6k. FEBS Lett 410(1):78–82

    Article  PubMed  CAS  Google Scholar 

  • 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):4159–4166

    Article  PubMed  CAS  Google Scholar 

  • Rao R, Buckner J et al. (2004) Mammalian target of rapamycin (mTOR) inhibitors as anti-cancer agents. Curr Cancer Drug Targets 4(8):621–635

    Article  PubMed  CAS  Google Scholar 

  • 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):2336–2347

    Article  PubMed  CAS  Google Scholar 

  • Reibel J (2003) Prognosis of oral pre-malignant lesions: significance of clinical, histopathological, and molecular biological characteristics. Crit Rev Oral Biol Med 14(1):47–62

    Article  PubMed  Google Scholar 

  • 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):18–22

    PubMed  CAS  Google Scholar 

  • Rhoads R (1993) Regulation of eukaryotic protein synthesis by initiation factors. J Biol Chem 268(5):3017–3020

    PubMed  CAS  Google Scholar 

  • 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):4309–4316

    Article  PubMed  CAS  Google Scholar 

  • 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 270:21176–21180

    Article  PubMed  CAS  Google Scholar 

  • Rowinsky E (2004) Targeting the molecular target of rapamycin (mTOR). Curr Opin Oncol 16(6):564–575

    Article  PubMed  CAS  Google Scholar 

  • 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-z

    Article  PubMed  Google Scholar 

  • 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):1296–1302

    Article  PubMed  CAS  Google Scholar 

  • Sarbassov D, Guertin D et al. (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307(5712):1098–1101

    Article  PubMed  CAS  Google Scholar 

  • Sarbassov D, Ali S et al. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159–168

    Article  PubMed  CAS  Google Scholar 

  • Scheid M, Woodgett J (2001) PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2(10):760–768

    Article  PubMed  CAS  Google Scholar 

  • 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):727–732

    CAS  Google Scholar 

  • Shantz L, Pegg A (1994) Overproduction of ornithine decarboxylase caused by relief of translational repression is associated with neoplastic transformation. Cancer Res 54:2313–2316

    PubMed  CAS  Google Scholar 

  • 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):406–411

    Article  PubMed  Google Scholar 

  • 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):5064–5073

    Article  PubMed  CAS  Google Scholar 

  • 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):77–85

    Article  PubMed  CAS  Google Scholar 

  • 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):7052–7058

    Article  PubMed  CAS  Google Scholar 

  • Thariat J, Yildirim G et al. (2007) Combination of radiotherapy with EGFR antagonists for head and neck carcinoma. Int J Clin Oncol 12(2):99–110

    Article  PubMed  CAS  Google Scholar 

  • Tsurutani J, Castillo S et al. (2005) Tobacco components stimulate Akt-dependent proliferation and NFkappaB-dependent survival in lung cancer cells. Carcinogenesis 26(7):1182–1195

    Article  PubMed  CAS  Google Scholar 

  • Vignot S, Faivre S et al. (2005) mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 16(4):525–537

    Article  PubMed  CAS  Google Scholar 

  • 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):1615–1622

    Article  PubMed  CAS  Google Scholar 

  • Vivanco I, Sawyers CL (2002) The phosphatidylinositol pathway in human cancer. Nat Rev Cancer 2(7):489–501

    Article  PubMed  CAS  Google Scholar 

  • Wan X, Harkavy B et al. (2007) Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26(13):1932–1940

    Article  PubMed  CAS  Google Scholar 

  • 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):139–146

    Article  PubMed  CAS  Google Scholar 

  • 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):14624–14631

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Li W et al. (2001) Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J 20(16):4370–4379

    Article  PubMed  CAS  Google Scholar 

  • Wee S, Jagani Z et al. (2009) PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res 69(10):OF1–OF8

    Article  CAS  Google Scholar 

  • 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):6841–6845

    PubMed  CAS  Google Scholar 

  • Wendel H, DeStanchina E et al. (2004) Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428(6980):332–337

    Article  PubMed  CAS  Google Scholar 

  • Wullschleger S, Loewith R et al. (2006) TOR signaling in growth and metabolism. Cell 124(3):471–484

    Article  PubMed  CAS  Google Scholar 

  • 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):4394–4399

    Article  PubMed  CAS  Google Scholar 

  • 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):1099–1107

    PubMed  CAS  Google Scholar 

  • 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 8:249–258

    Article  PubMed  Google Scholar 

  • Yun H, Bogaerts J et al. (2007) Clinical trial design limitations in head and neck squamous cell carcinomas. Curr Opin Oncol 19(3):210–215

    Article  PubMed  Google Scholar 

  • Zeng Z, Sarbassov D et al. (2007) Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109(8):3509–3512

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health Sciences Center, Shreveport, LA, USA

    Cherie-Ann O. Nathan

  2. Feist-Weiller Cancer Center, Shreveport, LA, USA

    Cherie-Ann O. Nathan

Authors
  1. Cheryl Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oleksandr Ekshyyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cherie-Ann O. Nathan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cherie-Ann O. Nathan .

Editor information

Editors and Affiliations

  1. Center for Molecular Toxicology &, Carcinogenesis, Pennsylvania State University, University Park, 16801, Pennsylvania, USA

    Adam B. Glick

  2. National Institute on Deafness &, Other Communication Disorders, National Institute of Health, Bethesda, 20892, Maryland, USA

    Carter Van Waes

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Clark, C., Ekshyyan, O., Nathan, CA.O. (2011). Effects and Therapeutic Potential of Targeting Dysregulated Signaling Axes in Squamous Cell Carcinoma: Another Kinase of Transcription and Mammalian Target of Rapamycin. In: Glick, A., Waes, C. (eds) Signaling Pathways in Squamous Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7203-3_18

Download citation

Publish with us

Policies and ethics

Search

Navigation