Targeting EGFR-PI3K-AKT-mTOR signaling enhances radiosensitivity in head and neck squamous cell carcinoma

Bibliography

• Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63(1):11-30
   PubMed Web of Science ®Google Scholar
• Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet 2008;371(9625):1695-709
   PubMed Web of Science ®Google Scholar
• D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007;356(19):1944-56
   PubMed Web of Science ®Google Scholar
• Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000;92(9):709-20
   PubMed Web of Science ®Google Scholar
• Sewell A, Brown B, Biktasova A, et al. Reverse-phase protein array profiling of oropharyngeal cancer and significance of PIK3CA mutations in HPV-associated head and neck cancer. Clin Cancer Res 2014;20(9):2300-11
   Google Scholar
• Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008;100(4):261-9
   PubMedGoogle Scholar
• Lassen P. The role of human papillomavirus in head and neck cancer and the impact on radiotherapy outcome. Radiother Oncol 2010;95(3):371-80
   PubMed Web of Science ®Google Scholar
• Lassen P, Eriksen JG, Hamilton-Dutoit S, et al. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol 2009;27(12):1992-8
   PubMed Web of Science ®Google Scholar
• Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus – associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 2006;24(5):736-47
   PubMed Web of Science ®Google Scholar
• Jemal A, Clegg LX, Ward E, et al. Annual report to the nation on the status of cancer, 1975-2001, with a special feature regarding survival. Cancer 2004;101(1):3-27
   PubMed Web of Science ®Google Scholar
• Vermorken JB, Specenier P. Optimal treatment for recurrent/metastatic head and neck cancer. Ann Oncol 2010;21(Suppl 7):vii252-61
   PubMed Web of Science ®Google Scholar
• Mao L, Hong WK, Papadimitrakopoulou VA. Focus on head and neck cancer. Cancer Cell 2004;5(4):311-16
   PubMedGoogle Scholar
• Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med 2001;345(26):1890-900
   PubMed Web of Science ®Google Scholar
• Pickering CR, Zhang J, Yoo SY, et al. Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Discov 2013;3(7):770-81
   PubMed Web of Science ®Google Scholar
• Iglesias-Bartolome R, Martin D, Gutkind JS. Exploiting the head and neck cancer oncogenome: widespread PI3K-mTOR pathway alterations and novel molecular targets. Cancer Discov 2013;3(7):722-5
   Google Scholar
• Agrawal N, Frederick MJ, Pickering CR, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 2011;333(6046):1154-7
   PubMed Web of Science ®Google Scholar
• Stransky N, Egloff AM, Tward AD, et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011;333(6046):1157-60
   PubMed Web of Science ®Google Scholar
• Dent P, Yacoub A, Contessa J, et al. Stress and radiation-induced activation of multiple intracellular signaling pathways. Radiat Res 2003;159(3):283-300
   PubMed Web of Science ®Google Scholar
• Hildebrandt MA, Lippman SM, Etzel CJ, et al. Genetic variants in the PI3K/PTEN/AKT/mTOR pathway predict head and neck cancer patient second primary tumor/recurrence risk and response to retinoid chemoprevention. Clin Cancer Res 2012;18(13):3705-13
   Google Scholar
• Lui VW, Hedberg ML, Li H, et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov 2013;3(7):761-9
   PubMed Web of Science ®Google Scholar
• Chiosea SI, Grandis JR, Lui VW, et al. PIK3CA, HRAS and PTEN in human papillomavirus positive oropharyngeal squamous cell carcinoma. BMC Cancer 2013;13:602
   Google Scholar
• Liu P, Cheng H, Roberts T, Zhao J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009;8(8):627-44
   PubMed Web of Science ®Google Scholar
• Herbst RS. Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys 2004;59(2 Suppl):21-6
   PubMed Web of Science ®Google Scholar
• Cully M, You H, Levine A, Mak T. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer 2006;6(3):184-92
   PubMed Web of Science ®Google Scholar
• Vivanco I, Sawyers C. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2(7):489-501
   PubMed Web of Science ®Google Scholar
• Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307(5712):1098-101
   PubMed Web of Science ®Google Scholar
• Di Maira G, Salvi M, Arrigoni G, et al. Protein kinase CK2 phosphorylates and upregulates Akt/PKB. Cell Death Differ 2005;12(6):668-77
   PubMed Web of Science ®Google Scholar
• Ozes O, Mayo L, Gustin J, et al. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 1999;401(6748):82-5
   PubMed Web of Science ®Google Scholar
• Tran H, Brunet A, Griffith E, Greenberg M. The many forks in FOXO’’’s road. Sci STKE 2003;2003(172):RE5
   Google Scholar
• Inoki K, Corradetti M, Guan K. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 2005;37(1):19-24
   PubMed Web of Science ®Google Scholar
• Gupta AK, McKenna WG, Weber CN, et al. Local recurrence in head and neck cancer: relationship to radiation resistance and signal transduction. Clin Cancer Res 2002;8(3):885-92
   PubMed Web of Science ®Google Scholar
• Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 2004;4(6):437-47
   PubMed Web of Science ®Google Scholar
• Bentzen SM, Atasoy BM, Daley FM, et al. Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial. J Clin Oncol 2005;23(24):5560-7
   PubMed Web of Science ®Google Scholar
• Nijkamp MM, Hoogsteen IJ, Span PN, et al. Spatial relationship of phosphorylated epidermal growth factor receptor and activated AKT in head and neck squamous cell carcinoma. Radiother Oncol 2011;101(1):165-70
   PubMed Web of Science ®Google Scholar
• Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006;368(9538):843-54
   PubMed Web of Science ®Google Scholar
• Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 2003;349(22):2091-8
   PubMed Web of Science ®Google Scholar
• Kaanders JH, Bussink J, van der Kogel AJ. Clinical studies of hypoxia modification in radiotherapy. Semin Radiat Oncol 2004;14(3):233-40
   Google Scholar
• Petersen C, Zips D, Krause M, et al. Repopulation of FaDu human squamous cell carcinoma during fractionated radiotherapy correlates with reoxygenation. Int J Radiat Oncol Biol Phys 2001;51(2):483-93
   Google Scholar
• Kim IA, Bae SS, Fernandes A, et al. Selective inhibition of Ras, phosphoinositide 3 kinase, and Akt isoforms increases the radiosensitivity of human carcinoma cell lines. Cancer Res 2005;65(17):7902-10
   Google Scholar
• Nijkamp MM, Span PN, Bussink J, Kaanders JH. Interaction of EGFR with the tumour microenvironment: implications for radiation treatment. Radiother Oncol 2013;108(1):17-23
   PubMed Web of Science ®Google Scholar
• Bussink J, Kaanders JH, van der Kogel AJ. Tumor hypoxia at the micro-regional level: clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers. Radiother Oncol 2003;67(1):3-15
   PubMed Web of Science ®Google Scholar
• Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 2007;26(2):225-39
   PubMed Web of Science ®Google Scholar
• Franovic A, Gunaratnam L, Smith K, et al. Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer. Proc Natl Acad Sci USA 2007;104(32):13092-7
   Google Scholar
• Nishi H, Nishi KH, Johnson AC. Early Growth Response-1 gene mediates up-regulation of epidermal growth factor receptor expression during hypoxia. Cancer Res 2002;62(3):827-34
   Google Scholar
• Rademakers SE, Span PN, Kaanders JH, et al. Molecular aspects of tumour hypoxia. Mol Oncol 2008;2(1):41-53
   PubMed Web of Science ®Google Scholar
• Semenza GL. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol 2000;35(2):71-103
   PubMed Web of Science ®Google Scholar
• Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 1993;53(15):3579-84
   PubMed Web of Science ®Google Scholar
• Grandis JR, Melhem MF, Gooding WE, et al. Levels of TGF-α and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 1998;90(11):824-32
   PubMedGoogle Scholar
• Chung CH, Ely K, McGavran L, et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol 2006;24(25):4170-6
   PubMed Web of Science ®Google Scholar
• Martin CL, Reshmi SC, Ried T, et al. Chromosomal imbalances in oral squamous cell carcinoma: examination of 31 cell lines and review of the literature. Oral Oncol 2008;44(4):369-82
   PubMed Web of Science ®Google Scholar
• Gollin SM. Chromosomal alterations in squamous cell carcinomas of the head and neck: window to the biology of disease. Head Neck 2001;23(3):238-53
   Google Scholar
• Temam S, Kawaguchi H, El-Naggar AK, et al. Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. J Clin Oncol 2007;25(16):2164-70
   PubMed Web of Science ®Google Scholar
• Bigner SH, Humphrey PA, Wong AJ, et al. Characterization of the epidermal growth factor receptor in human glioma cell lines and xenografts. Cancer Res 1990;50(24):8017-22
   PubMed Web of Science ®Google Scholar
• Sugawa N, Ekstrand AJ, James CD, Collins VP. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc Natl Acad Sci USA 1990;87(21):8602-6
   PubMed Web of Science ®Google Scholar
• Nishikawa R, Ji XD, Harmon RC, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci USA 1994;91(16):7727-31
   PubMed Web of Science ®Google Scholar
• Diedrich U, Lucius J, Baron E, et al. Distribution of epidermal growth factor receptor gene amplification in brain tumours and correlation to prognosis. J Neurol 1995;242(10):683-8
   Google Scholar
• Sok JC, Coppelli FM, Thomas SM, et al. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res 2006;12(17):5064-73
   PubMed Web of Science ®Google Scholar
• Loeffler-Ragg J, Schwentner I, Sprinzl GM, Zwierzina H. EGFR inhibition as a therapy for head and neck squamous cell carcinoma. Expert Opin Investig Drugs 2008;17(10):1517-31
   PubMed Web of Science ®Google Scholar
• Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5(5):341-54
   PubMed Web of Science ®Google Scholar
• Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354(6):567-78
   PubMed Web of Science ®Google Scholar
• Vermorken J, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007;25(16):2171-7
   PubMed Web of Science ®Google Scholar
• Allan DG. Nimotuzumab: evidence of clinical benefit without rash. Oncologist 2005;10(9):760-1
   Google Scholar
• Li T, Perez-Soler R. Skin toxicities associated with epidermal growth factor receptor inhibitors. Target Oncol 2009;4(2):107-19
   PubMed Web of Science ®Google Scholar
• Racca P, Fanchini L, Caliendo V, et al. Efficacy and skin toxicity management with cetuximab in metastatic colorectal cancer: outcomes from an oncologic/dermatologic cooperation. Clin Colorectal Cancer 2008;7(1):48-54
   Google Scholar
• Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005;16(9):1425-33
   PubMed Web of Science ®Google Scholar
• Crombet T, Osorio M, Cruz T, et al. Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients. J Clin Oncol 2004;22(9):1646-54
   PubMed Web of Science ®Google Scholar
• Ramakrishnan MS, Eswaraiah A, Crombet T, et al. Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin. MAbs 2009;1(1):41-8
   PubMed Web of Science ®Google Scholar
• Rodriguez MO, Rivero TC, del Castillo Bahi R, et al. Nimotuzumab plus radiotherapy for unresectable squamous-cell carcinoma of the head and neck. Cancer Biol Ther 2010;9(5):343-9
   PubMed Web of Science ®Google Scholar
• Sheridan MT, O’Dwyer T, Seymour CB, Mothersill CE. Potential indicators of radiosensitivity in squamous cell carcinoma of the head and neck. Radiat Oncol Investig 1997;5(4):180-6
   PubMedGoogle Scholar
• Milas L, Fan Z, Andratschke NH, Ang KK. Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. Int J Radiat Oncol Biol Phys 2004;58(3):966-71
   Google Scholar
• Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002;62(24):7350-6
   PubMed Web of Science ®Google Scholar
• Ang KK, Andratschke NH, Milas L. Epidermal growth factor receptor and response of head-and-neck carcinoma to therapy. Int J Radiat Oncol Biol Phys 2004;58(3):959-65
   PubMed Web of Science ®Google Scholar
• Kwok TT, Sutherland RM. Enhancement of sensitivity of human squamous carcinoma cells to radiation by epidermal growth factor. J Natl Cancer Inst 1989;81(13):1020-4
   Google Scholar
• Bonner JA, Maihle NJ, Folven BR, et al. The interaction of epidermal growth factor and radiation in human head and neck squamous cell carcinoma cell lines with vastly different radiosensitivities. Int J Radiat Oncol Biol Phys 1994;29(2):243-7
   PubMed Web of Science ®Google Scholar
• Balaban N, Moni J, Shannon M, et al. The effect of ionizing radiation on signal transduction: antibodies to EGF receptor sensitize A431 cells to radiation. Biochim Biophys Acta 1996;1314(1-2):147-56
   PubMed Web of Science ®Google Scholar
• Schmidt-Ullrich RK, Valerie K, Fogleman PB, Walters J. Radiation-induced autophosphorylation of epidermal growth factor receptor in human malignant mammary and squamous epithelial cells. Radiat Res 1996;145(1):81-5
   Google Scholar
• Schmidt-Ullrich RK, Mikkelsen RB, Dent P, et al. Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene 1997;15(10):1191-7
   PubMed Web of Science ®Google Scholar
• Dent P, Reardon DB, Park JS, et al. Radiation-induced release of transforming growth factor alpha activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death. Mol Biol Cell 1999;10(8):2493-506
   PubMed Web of Science ®Google Scholar
• Contessa JN, Hampton J, Lammering G, et al. Ionizing radiation activates Erb-B receptor dependent Akt and p70 S6 kinase signaling in carcinoma cells. Oncogene 2002;21(25):4032-41
   PubMed Web of Science ®Google Scholar
• Dittmann K, Mayer C, Fehrenbacher B, et al. Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase. J Biol Chem 2005;280(35):31182-9
   PubMed Web of Science ®Google Scholar
• Akimoto T, Hunter NR, Buchmiller L, et al. Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. Clin Cancer Res 1999;5(10):2884-90
   PubMed Web of Science ®Google Scholar
• Moscatello DK, Holgado-Madruga M, Emlet DR, et al. Constitutive activation of phosphatidylinositol 3-kinase by a naturally occurring mutant epidermal growth factor receptor. J Biol Chem 1998;273(1):200-6
   PubMed Web of Science ®Google Scholar
• Mukherjee B, McEllin B, Camacho CV, et al. EGFRvIII and DNA double-strand break repair: a molecular mechanism for radioresistance in glioblastoma. Cancer Res 2009;69(10):4252-9
   PubMed Web of Science ®Google Scholar
• Lammering G, Hewit TH, Valerie K, et al. EGFRvIII-mediated radioresistance through a strong cytoprotective response. Oncogene 2003;22(36):5545-53
   PubMed Web of Science ®Google Scholar
• Li B, Yuan M, Kim IA, et al. Mutant epidermal growth factor receptor displays increased signaling through the phosphatidylinositol-3 kinase/AKT pathway and promotes radioresistance in cells of astrocytic origin. Oncogene 2004;23(26):4594-602
   PubMed Web of Science ®Google Scholar
• Massarelli E, Liu DD, Lee JJ, et al. Akt activation correlates with adverse outcome in tongue cancer. Cancer 2005;104(11):2430-6
   Google Scholar
• Bussink J, van der Kogel AJ, Kaanders JH. Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol 2008;9(3):288-96
   PubMed Web of Science ®Google Scholar
• Lieber MR, Ma Y, Pannicke U, Schwarz K. Mechanism and regulation of human non-homologous DNA end-joining. Nat Rev Mol Cell Biol 2003;4(9):712-20
   PubMed Web of Science ®Google Scholar
• Toulany M, Kasten-Pisula U, Brammer I, et al. Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair. Clin Cancer Res 2006;12(13):4119-26
   PubMedGoogle Scholar
• Webster L, Hodgkiss RJ, Wilson GD. Cell cycle distribution of hypoxia and progression of hypoxic tumour cells in vivo. Br J Cancer 1998;77(2):227-34
   PubMed Web of Science ®Google Scholar
• Hoogsteen IJ, Marres HA, Wijffels KI, et al. Colocalization of carbonic anhydrase 9 expression and cell proliferation in human head and neck squamous cell carcinoma. Clin Cancer Res 2005;11(1):97-106
   Google Scholar
• Harris AL. Hypoxia – a key regulatory factor in tumour growth. Nat Rev Cancer 2002;2(1):38-47
   PubMed Web of Science ®Google Scholar
• Brizel DM, Sibley GS, Prosnitz LR, et al. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997;38(2):285-9
   PubMed Web of Science ®Google Scholar
• Nordsmark M, Bentzen SM, Rudat V, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 2005;77(1):18-24
   PubMed Web of Science ®Google Scholar
• Dragowska WH, Verreault M, Yapp DT, et al. Decreased levels of hypoxic cells in gefitinib treated ER+ HER-2 overexpressing MCF-7 breast cancer tumors are associated with hyperactivation of the mTOR pathway: therapeutic implications for combination therapy with rapamycin. Breast Cancer Res Treat 2007;106(3):319-31
   Google Scholar
• Krause M, Ostermann G, Petersen C, et al. Decreased repopulation as well as increased reoxygenation contribute to the improvement in local control after targeting of the EGFR by C225 during fractionated irradiation. Radiother Oncol 2005;76(2):162-7
   Google Scholar
• Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol (1985) 2000;88(4):1474-80
   PubMed Web of Science ®Google Scholar
• Zhong H, Chiles K, Feldser D, et al. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000;60(6):1541-5
   PubMed Web of Science ®Google Scholar
• Bleau AM, Hambardzumyan D, Ozawa T, et al. PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 2009;4(3):226-35
   PubMed Web of Science ®Google Scholar
• Zhang M, Atkinson RL, Rosen JM. Selective targeting of radiation-resistant tumor-initiating cells. Proc Natl Acad Sci USA 2010;107(8):3522-7
   Google Scholar
• Bruzzese F, Leone A, Rocco M, et al. HDAC inhibitor vorinostat enhances the antitumor effect of gefitinib in squamous cell carcinoma of head and neck by modulating ErbB receptor expression and reverting EMT. J Cell Physiol 2011;226(9):2378-90
   PubMed Web of Science ®Google Scholar
• Hong KO, Kim JH, Hong JS, et al. Inhibition of Akt activity induces the mesenchymal-to-epithelial reverting transition with restoring E-cadherin expression in KB and KOSCC-25B oral squamous cell carcinoma cells. J Exp Clin Cancer Res 2009;28:28
   PubMedGoogle Scholar
• Li B, Yuan M, Kim IA, et al. Mutant epidermal growth factor receptor displays increased signaling through the phosphatidylinositol-3 kinase/AKT pathway and promotes radioresistance in cells of astrocytic origin. Oncogene 2004;23(26):4594-602
   PubMed Web of Science ®Google Scholar
• Nakamura JL, Karlsson A, Arvold ND, et al. PKB/Akt mediates radiosensitization by the signaling inhibitor LY294002 in human malignant gliomas. J Neurooncol 2005;71(3):215-22
   Google Scholar
• Freudlsperger C, Horn D, Weissfuss S, et al. Phosphorylation of AKT(Ser473) serves as an independent prognostic marker for radiosensitivity in advanced head and neck squamous cell carcinoma. Int J Cancer 2014. [ Epub ahead of print]
   Google Scholar
• Xue W, Meylan E, Oliver TG, et al. Response and resistance to NF-kappaB inhibitors in mouse models of lung adenocarcinoma. Cancer Discov 2011;1(3):236-47
   PubMed Web of Science ®Google Scholar
• Fujita T, Doihara H, Washio K, et al. Proteasome inhibitor bortezomib increases PTEN expression and enhances trastuzumab-induced growth inhibition in trastuzumab-resistant cells. Anticancer Drugs 2006;17(4):455-62
   PubMed Web of Science ®Google Scholar
• Weber CN, Cerniglia GJ, Maity A, Gupta AK. Bortezomib sensitizes human head and neck carcinoma cells SQ20B to radiation. Cancer Biol Ther 2007;6(2):156-9
   PubMed Web of Science ®Google Scholar
• Yu C, Friday BB, Lai JP, et al. Cytotoxic synergy between the multikinase inhibitor sorafenib and the proteasome inhibitor bortezomib in vitro: induction of apoptosis through Akt and c-Jun NH2-terminal kinase pathways. Mol Cancer Ther 2006;5(9):2378-87
   PubMed Web of Science ®Google Scholar
• Kubicek GJ, Axelrod RS, Machtay M, et al. Phase I trial using the proteasome inhibitor bortezomib and concurrent chemoradiotherapy for head-and-neck malignancies. Int J Radiat Oncol Biol Phys 2012;83(4):1192-7
   Google Scholar
• Bowles DW, Ma WW, Senzer N, et al. A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours. Br J Cancer 2013;109(5):1085-92
   PubMed Web of Science ®Google Scholar
• Bowles DW, Senzer N, Hausman D, et al. A multicenter phase 1 study of PX-866 and cetuximab in patients with metastatic colorectal carcinoma or recurrent/metastatic squamous cell carcinoma of the head and neck. Invest New Drugs 2014;32(6):1197-203
   PubMed Web of Science ®Google Scholar
• Ekshyyan O, Rong Y, Rong X, et al. Comparison of radiosensitizing effects of the mammalian target of rapamycin inhibitor CCI-779 to cisplatin in experimental models of head and neck squamous cell carcinoma. Mol Cancer Ther 2009;8(8):2255-65
   PubMed Web of Science ®Google Scholar
• Cerniglia GJ, Karar J, Tyagi S, et al. Inhibition of autophagy as a strategy to augment radiosensitization by the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Mol Pharmacol 2012;82(6):1230-40
   PubMed Web of Science ®Google Scholar
• Kim KW, Mutter RW, Cao C, et al. Autophagy for cancer therapy through inhibition of pro-apoptotic proteins and mammalian target of rapamycin signaling. J Biol Chem 2006;281(48):36883-90
   Google Scholar
• O Farrell F, Rusten TE, Stenmark H. Phosphoinositide 3-kinases as accelerators and brakes of autophagy. FEBS J 2013;280(24):6322-37
   Google Scholar
• Kim KW, Myers CJ, Jung DK, Lu B. NVP-BEZ-235 enhances radiosensitization via blockade of the PI3K/mTOR pathway in cisplatin-resistant non-small cell lung carcinoma. Genes Cancer 2014;5(7-8):293-302
   PubMedGoogle Scholar
• Lechner M, Frampton GM, Fenton T, et al. Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors. Genome Med 2013;5(5):49
   PubMedGoogle Scholar
• Coppock JD, Wieking BG, Molinolo AA, et al. Improved clearance during treatment of HPV-positive head and neck cancer through mTOR inhibition. Neoplasia 2013;15(6):620-30
   Google Scholar
• Molinolo AA, Marsh C, El Dinali M, et al. mTOR as a molecular target in HPV-associated oral and cervical squamous carcinomas. Clin Cancer Res 2012;18(9):2558-68
   PubMed Web of Science ®Google Scholar
• Kuo WL, Sharifi MN, Lingen MW, et al. p62/SQSTM1 accumulation in squamous cell carcinoma of head and neck predicts sensitivity to phosphatidylinositol 3-kinase pathway inhibitors. PLoS One 2014;9(3):e90171
   Google Scholar
• Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354(6):567-78
   PubMed Web of Science ®Google Scholar