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Overcoming Inherent Resistance to Proteasome Inhibitors in Head and Neck Cancer: Challenges and New Approaches

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Resistance to Proteasome Inhibitors in Cancer

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT))

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Abstract

Advanced stage head and neck squamous cell carcinoma (HNSCC) is a relatively common human malignancy that generally carries a poor prognosis. Despite the in vitro sensitivity of HNSCC cells to proteasome inhibitors, clinical testing of bortezomib in HNSCC patients has encountered obstacles of inherent resistance and adverse toxicities. To combat these difficulties, current efforts are focused on developing strategies that co-target the proteasome and other key signaling pathways. In addition, new proteasome inhibitors are being developed which exhibit reduced side effects in patients. This chapter will review our current understanding of the pathology and biology of HNSCC, findings from preclinical studies of proteasome inhibitors in HNSCC models, results from early-stage clinical testing of proteasome inhibitors in HNSCC patients, and the unique opportunities for proteasome targeting in human papillomavirus-positive HNSCC.

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Abbreviations

HNSCC:

Head and neck squamous cell carcinoma

HPV:

Human papillomavirus

BMI:

Body mass index

RT:

Radiation therapy

CRT:

Chemoradiation

FDA:

Food and Drug Administration

EGFR:

Epidermal growth factor receptor

PARP:

Poly(ADP-ribose) polymerase

MTD:

Maximum tolerated dose

ROS:

Reactive oxygen species

HDAC:

Histone deacetylase

PR:

Partial response

SD:

Stable disease

PD:

Progressive disease

References

  1. Mehanna H, Paleri V, West CML, Nutting C (2010) Head and neck cancer—Part 1: Epidemiology, presentation, and prevention. BMJ 341:c4684–c4684

    PubMed  CAS  Google Scholar 

  2. Sturgis EM, Ang KK (2011) The epidemic of HPV-associated oropharyngeal cancer is here: is it time to change our treatment paradigms? Journal of the National Comprehensive Cancer Network : JNCCN 9(6):665–673

    PubMed  Google Scholar 

  3. Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, Jiang B, Goodman MT, Sibug-Saber M, Cozen W, Liu L, Lynch CF, Wentzensen N, Jordan RC, Altekruse S, Anderson WF, Rosenberg PS, Gillison ML (2011) Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 29(32):4294–4301

    PubMed  PubMed Central  Google Scholar 

  4. Sturgis EM, Cinciripini PM (2007) Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers? Cancer 110:1429–1435

    PubMed  Google Scholar 

  5. Blot WJ, Mclaughlin JK, Winn DM, Austin DF, Greenberg RS, Bernstein L, Schoenberg JB, Stemhagen A, Fraumeni JF (1988) smoking and drinking in relation to oral and pharyngeal cancer smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res. 48(11): 3282-7.

    Google Scholar 

  6. Hashibe M, Brennan P, Benhamou S, Castellsague X, Chen C, Curado MP, Dal Maso L, Daudt AW, Fabianova E, Fernandez L, Wünsch-Filho V, Franceschi S, Hayes RB, Herrero R, Koifman S, La Vecchia C, Lazarus P, Levi F, Mates D, Matos E, Menezes A, Muscat J, Eluf-Neto J, Olshan AF, Rudnai P, Schwartz SM, Smith E, Sturgis EM, Szeszenia-Dabrowska N, Talamini R, Wei Q, Winn DM, Zaridze D, Zatonski W, Zhang Z-F, Berthiller J, Boffetta P (2007) Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst 99:777–789

    PubMed  Google Scholar 

  7. Wyss A, Hashibe M, Chuang S-C, Amy Lee Y-C, Zhang Z-F, Yu G-P, Winn DM, Wei Q, Talamini R, Szeszenia-Dabrowska N, Sturgis EM, Smith E, Shangina O, Schwartz SM, Schantz S, Rudnai P, Purdue MP, Eluf-Neto J, Muscat J, Morgenstern H, Michaluart P, Menezes A, Matos E, Mates IN, Lissowska J, Levi F, Lazarus P, La Vecchia C, Koifman S, Herrero R, Hayes RB, Franceschi S, Wünsch-Filho V, Fernandez L, Fabianova E, Daudt AW, Dal Maso L, Curado MP, Chen C, Castellsague X, de Carvalho MB, Cadoni G, Boccia S, Brennan P, Boffetta P, Olshan AF (2013) Cigarette, Cigar, and Pipe Smoking and the Risk of Head and Neck Cancers: Pooled Analysis in the International Head and Neck Cancer Epidemiology Consortium. American journal of epidemiology:1-12

    Google Scholar 

  8. Sharan RN, Mehrotra R, Choudhury Y, Asotra K (2012) Association of betel nut with carcinogenesis: revisit with a clinical perspective. PLoS One 7:e42759

    PubMed  CAS  PubMed Central  Google Scholar 

  9. Purdue MP, Hashibe M, Berthiller J, La Vecchia C, Dal Maso L, Herrero R, Franceschi S, Castellsague X, Wei Q, Sturgis EM, Morgenstern H, Zhang Z-F, Levi F, Talamini R, Smith E, Muscat J, Lazarus P, Schwartz SM, Chen C, Neto JE, Wünsch-Filho V, Zaridze D, Koifman S, Curado MP, Benhamou S, Matos E, Szeszenia-Dabrowska N, Olshan AF, Lence J, Menezes A, Daudt AW, Mates IN, Pilarska A, Fabianova E, Rudnai P, Winn D, Ferro G, Brennan P, Boffetta P, Hayes RB (2009) Type of alcoholic beverage and risk of head and neck cancer—a pooled analysis within the INHANCE Consortium. Am J Epidemiol 169:132–142

    PubMed  PubMed Central  Google Scholar 

  10. Hammarstedt L, Lindquist D, Dahlstrand H, Romanitan M, Dahlgren LO, Joneberg J, Creson N, Lindholm J, Ye W, Dalianis T, Munck-Wikland E (2006) Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer. International journal of cancer Journal international du cancer 119:2620–2623

    PubMed  CAS  Google Scholar 

  11. Shiboski CH, Schmidt BL, Jordan RC (2005) Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20-44 years. Cancer 103(9):1843–1849

    PubMed  Google Scholar 

  12. Ca M, La L (2010) Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer 10:550–560

    Google Scholar 

  13. Hiraki A, Matsuo K, Suzuki T, Kawase T, Tajima K (2008) Teeth loss and risk of cancer at 14 common sites in Japanese. Cancer epidemiology biomarkers prevention a publication of the American Association for Cancer Research cosponsored by the American Society of Preventive Oncology 17:1222–1227

    Google Scholar 

  14. Wang R-S, Hu X-Y, Gu W-J, Hu Z, Wei B (2013) Tooth loss and risk of head and neck cancer: a meta-analysis. PLoS One 8:e71122

    PubMed  CAS  PubMed Central  Google Scholar 

  15. Freedman ND, Park Y, Subar AF, Hollenbeck AR, Leitzmann MF, Schatzkin A, Abnet CC (2008) Fruit and vegetable intake and head and neck cancer risk in a large United States prospective cohort study. International journal of cancer Journal international du cancer 122:2330–2336

    PubMed  CAS  Google Scholar 

  16. Gaudet MM, Olshan AF, Chuang S-C, Berthiller J, Zhang Z-F, Lissowska J, Zaridze D, Winn DM, Wei Q, Talamini R, Szeszenia-Dabrowska N, Sturgis EM, Schwartz SM, Rudnai P, Eluf-Neto J, Muscat J, Morgenstern H, Menezes A, Matos E, Bucur A, Levi F, Lazarus P, La Vecchia C, Koifman S, Kelsey K, Herrero R, Hayes RB, Franceschi S, Wunsch-Filho V, Fernandez L, Fabianova E, Daudt AW, Dal Maso L, Curado MP, Chen C, Castellsague X, Benhamou S, Boffetta P, Brennan P, Hashibe M (2010) Body mass index and risk of head and neck cancer in a pooled analysis of case-control studies in the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. Int J Epidemiol 39:1091–1102

    PubMed  PubMed Central  Google Scholar 

  17. Carrau R, Zimmer L, Myers EN (2006) Neoplasm of the nose and paranasal sinuses. Lippincott-Raven, Philadelphia

    Google Scholar 

  18. Tsai CJ, Hofstede TM, Sturgis EM, Garden AS, Lindberg ME, Wei Q, Tucker SL, Dong L (2013) Osteoradionecrosis and radiation dose to the mandible in patients with oropharyngeal cancer. Int J Radiat Oncol Biol Phys 85(2):415–420

    PubMed  Google Scholar 

  19. Higgins KM (2011) What treatment for early-stage glottic carcinoma among adult patients: CO2 endolaryngeal laser excision versus standard fractionated external beam radiation is superior in terms of cost utility? Laryngoscope 121(1):116–134

    PubMed  Google Scholar 

  20. Peeters AJ, van Gogh CD, Goor KM, Verdonck-de Leeuw IM, Langendijk JA, Mahieu HF (2004) Health status and voice outcome after treatment for T1a glottic carcinoma. Eur Arch Otorhinolaryngol 261(10):534–540

    PubMed  Google Scholar 

  21. Chen AM, Vaughan A, Narayan S, Vijayakumar S (2008) Palliative radiation therapy for head and neck cancer: toward an optimal fractionation scheme. Head Neck 30(12):1586–1591

    PubMed  Google Scholar 

  22. Genden EM (2012) The role for surgical management of HPV-related oropharyngeal carcinoma. Head Neck Pathol 6(Suppl 1):S98–103

    PubMed  Google Scholar 

  23. Wolf G, Hong W, Fisher S, Urba S (1991) Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 324:1685

    Google Scholar 

  24. Raol N, Hutcheson KA, Lewin JS, Kupferman ME (2013) Surgical management of the non-functional larynx after organ preservation therapy. J Otol Rhinol 2(1)

    Google Scholar 

  25. Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre J-L, Greiner RH, Giralt J, Maingon P, Rolland F, Bolla M, Cognetti F, Bourhis J, Kirkpatrick A, van Glabbeke M (2004) Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350:1945–1952

    PubMed  CAS  Google Scholar 

  26. Zhang L, Zhao C, Peng PJ, Lu LX, Huang PY, Han F, Wu SX (2005) Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. J Clin Oncol 23(33):8461–8468

    PubMed  CAS  Google Scholar 

  27. Argiris A, Karamouzis MV, Raben D, Ferris RL (2008) Head and neck cancer. Lancet 371:1695–1709

    PubMed  CAS  Google Scholar 

  28. Pignon J-P, le Maître A, Maillard E, Bourhis J (2009) Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 92:4–14

    Google Scholar 

  29. Burtness B, Ma G, Flood W, Mattar B, Aa F (2005) Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol 23:8646–8654

    PubMed  Google Scholar 

  30. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354(6):567–578

    PubMed  CAS  Google Scholar 

  31. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer H-R, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127

    PubMed  CAS  Google Scholar 

  32. Ang KK ZQ, Rosenthal DI, Nguyen-Tan P, Sherman EJ, Weber RS, Galvin JM, Schwartz DL, El-Naggar AK, Gillison ML, Jordan R, List MA, Konski AA, Thorstad WL, Trotti A, BeitlerJJ, Garden AS, Spanos WJ, Yom SS and RS Alelrod (2011) A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC).

    Google Scholar 

  33. Chen LF, Cohen EE, Grandis JR (2010) New strategies in head and neck cancer: understanding resistance to epidermal growth factor receptor inhibitors. Clin Cancer Res 16(9):2489–2495

    PubMed  CAS  PubMed Central  Google Scholar 

  34. Adams J, Kauffman M (2004) Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest 22(2):304–311

    PubMed  CAS  Google Scholar 

  35. Bross PF, Kane R, Farrell AT, Abraham S, Benson K, Brower ME, Bradley S, Gobburu JV, Goheer A, Lee SL, Leighton J, Liang CY, Lostritto RT, McGuinn WD, Morse DE, Rahman A, Rosario LA, Verbois SL, Williams G, Wang YC, Pazdur R (2004) Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin Cancer Res 10(12 Pt 1):3954–3964

    PubMed  CAS  Google Scholar 

  36. Richardson PG, Mitsiades C, Hideshima T, Anderson KC (2006) Bortezomib: proteasome inhibition as an effective anticancer therapy. Annu Rev Med 57:33–47

    PubMed  CAS  Google Scholar 

  37. Sayers TJ, Brooks AD, Koh CY, Ma W, Seki N, Raziuddin A, Blazar BR, Zhang X, Elliott PJ, Murphy WJ (2003) The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP. Blood 102(1):303–310

    PubMed  CAS  Google Scholar 

  38. Nikrad M, Johnson T, Puthalalath H, Coultas L, Adams J, Kraft AS (2005) The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-only proteins Bik and Bim. Mol Cancer Ther 4(3):443–449

    PubMed  CAS  Google Scholar 

  39. Qin JZ, Ziffra J, Stennett L, Bodner B, Bonish BK, Chaturvedi V, Bennett F, Pollock PM, Trent JM, Hendrix MJ, Rizzo P, Miele L, Nickoloff BJ (2005) Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells. Cancer Res 65(14): 6282–6293

    Google Scholar 

  40. Zhu H, Guo W, Zhang L, Wu S, Teraishi F, Davis JJ, Dong F, Fang B (2005) Proteasome inhibitors-mediated TRAIL resensitization and Bik accumulation. Cancer Biol Ther 4(7):781–786

    PubMed  CAS  PubMed Central  Google Scholar 

  41. Zhu H, Zhang L, Dong F, Guo W, Wu S, Teraishi F, Davis JJ, Chiao PJ, Fang B (2005) Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors. Oncogene 24(31):4993–4999

    PubMed  CAS  PubMed Central  Google Scholar 

  42. Perez-Galan P, Roue G, Villamor N, Montserrat E, Campo E, Colomer D (2006) The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. Blood 107(1):257–264

    PubMed  CAS  Google Scholar 

  43. Liu X, Yue P, Chen S, Hu L, Lonial S, Khuri FR, Sun SY (2007) The proteasome inhibitor PS-341 (bortezomib) up-regulates DR5 expression leading to induction of apoptosis and enhancement of TRAIL-induced apoptosis despite up-regulation of c-FLIP and survivin expression in human NSCLC cells. Cancer Res 67(10):4981–4988

    PubMed  CAS  Google Scholar 

  44. Perez-Galan P, Roue G, Villamor N, Campo E, Colomer D (2007) The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak. Blood 109(10):4441–4449

    PubMed  CAS  Google Scholar 

  45. Voortman J, Checinska A, Giaccone G, Rodriguez JA, Kruyt FA (2007) Bortezomib, but not cisplatin, induces mitochondria-dependent apoptosis accompanied by up-regulation of noxa in the non-small cell lung cancer cell line NCI-H460. Mol Cancer Ther 6(3):1046–1053

    PubMed  CAS  Google Scholar 

  46. Sunwoo JB, Chen Z, Dong G, Yeh N, Crowl Bancroft C, Sausville E, Adams J, Elliott P, Van Waes C (2001) Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer Res 7(5):1419–1428

    PubMed  CAS  Google Scholar 

  47. Fribley A, Zeng Q, Wang CY (2004) Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells. Mol Cell Biol 24(22):9695–9704

    PubMed  CAS  PubMed Central  Google Scholar 

  48. Chen Z, Ricker JL, Malhotra PS, Nottingham L, Bagain L, Lee TL, Yeh NT, Van Waes C (2008) Differential bortezomib sensitivity in head and neck cancer lines corresponds to proteasome, nuclear factor-kappaB and activator protein-1 related mechanisms. Mol Cancer Ther 7(7):1949–1960

    PubMed  CAS  PubMed Central  Google Scholar 

  49. Li C, Li R, Grandis JR, Johnson DE (2008) Bortezomib induces apoptosis via Bim and Bik up-regulation and synergizes with cisplatin in the killing of head and neck squamous cell carcinoma cells. Mol Cancer Ther 7(6):1647–1655

    PubMed  CAS  PubMed Central  Google Scholar 

  50. Lin YC, Chen KC, Chen CC, Cheng AL, Chen KF (2012) CIP2A-mediated Akt activation plays a role in bortezomib-induced apoptosis in head and neck squamous cell carcinoma cells. Oral Oncol 48(7):585–593

    PubMed  CAS  Google Scholar 

  51. Yang X (2012) Proteasome inhibitor bortezomi-induced the apoptosis of laryngeal squamous cell carcinoma Hep-2 cell line via disrupting redox equilibrium. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 66(8):607–611

    CAS  Google Scholar 

  52. Li C, Johnson DE (2013) Liberation of functional p53 by proteasome inhibition in human papilloma virus-positive head and neck squamous cell carcinoma cells promotes apoptosis and cell cycle arrest. Cell Cycle 12(6):923–934

    PubMed  CAS  PubMed Central  Google Scholar 

  53. Yin D, Zhou H, Kumagai T, Liu G, Ong JM, Black KL, Koeffler HP (2005) Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM). Oncogene 24(3):344–354

    PubMed  CAS  Google Scholar 

  54. Huang C, Hu X, Wang L, Lu S, Cheng H, Song X, Wang J, Yang J (2012) Bortezomib suppresses the growth of leukemia cells with Notch1 overexpression in vivo and in vitro. Cancer Chemother Pharmacol 70(6):801–809

    PubMed  CAS  Google Scholar 

  55. Hutter G, Rieken M, Pastore A, Weigert O, Zimmermann Y, Weinkauf M, Hiddemann W, Dreyling M (2012) The proteasome inhibitor bortezomib targets cell cycle and apoptosis and acts synergistically in a sequence-dependent way with chemotherapeutic agents in mantle cell lymphoma. Ann Hematol 91(6):847–856

    PubMed  CAS  Google Scholar 

  56. Lorch JH, Thomas TO, Schmoll HJ (2007) Bortezomib inhibits cell-cell adhesion and cell migration and enhances epidermal growth factor receptor inhibitor-induced cell death in squamous cell cancer. Cancer Res 67(2):727–734

    PubMed  CAS  Google Scholar 

  57. Orlowski RZ, Nagler A, Sonneveld P, Blade J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL (2007) Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 25(25):3892–3901

    PubMed  CAS  Google Scholar 

  58. Richardson PG, Briemberg H, Jagannath S, Wen PY, Barlogie B, Berenson J, Singhal S, Siegel DS, Irwin D, Schuster M, Srkalovic G, Alexanian R, Rajkumar SV, Limentani S, Alsina M, Orlowski RZ, Najarian K, Esseltine D, Anderson KC, Amato AA (2006) Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 24(19):3113–3120

    PubMed  CAS  Google Scholar 

  59. Cavaletti G, Jakubowiak AJ Peripheral neuropathy during bortezomib treatment of multiple myeloma: a review of recent studies. Leuk Lymphoma 51 (7):1178-1187

    Google Scholar 

  60. Corso A, Mangiacavalli S, Varettoni M, Pascutto C, Zappasodi P, Lazzarino M Bortezomib-induced peripheral neuropathy in multiple myeloma: a comparison between previously treated and untreated patients. Leuk Res 34 (4):471-474

    Google Scholar 

  61. Arastu-Kapur S, Anderl JL, Kraus M, Parlati F, Shenk KD, Lee SJ, Muchamuel T, Bennett MK, Driessen C, Ball AJ, Kirk CJ Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res 17 (9):2734-2743

    Google Scholar 

  62. Zang Y, Thomas SM, Chan ET, Kirk CJ, Freilino ML, DeLancey HM, Grandis JR, Li C, Johnson DE (2012) Carfilzomib and ONX 0912 inhibit cell survival and tumor growth of head and neck cancer and their activities are enhanced by suppression of Mcl-1 or autophagy. Clin Cancer Res 18(20):5639–5649

    PubMed  CAS  PubMed Central  Google Scholar 

  63. Zang Y, Thomas SM, Chan ET, Kirk CJ, Freilino ML, DeLancey HM, Grandis JR, Li C, Johnson DE (2012) The next generation proteasome inhibitors carfilzomib and oprozomib activate prosurvival autophagy via induction of the unfolded protein response and ATF4. Autophagy 8(12):1873–1874

    PubMed  CAS  PubMed Central  Google Scholar 

  64. Demo SD, Kirk CJ, Aujay MA, Buchholz TJ, Dajee M, Ho MN, Jiang J, Laidig GJ, Lewis ER, Parlati F, Shenk KD, Smyth MS, Sun CM, Vallone MK, Woo TM, Molineaux CJ, Bennett MK (2007) Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 67(13):6383–6391

    PubMed  CAS  Google Scholar 

  65. O'Connor OA, Stewart AK, Vallone M, Molineaux CJ, Kunkel LA, Gerecitano JF, Orlowski RZ (2009) A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res 15(22):7085–7091

    PubMed  PubMed Central  Google Scholar 

  66. Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk KD, Sun CM, Demo SD, Bennett MK, van Leeuwen FW, Chanan-Khan AA, Orlowski RZ (2007) Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 110(9):3281–3290

    PubMed  CAS  PubMed Central  Google Scholar 

  67. Zhou HJ, Aujay MA, Bennett MK, Dajee M, Demo SD, Fang Y, Ho MN, Jiang J, Kirk CJ, Laidig GJ, Lewis ER, Lu Y, Muchamuel T, Parlati F, Ring E, Shenk KD, Shields J, Shwonek PJ, Stanton T, Sun CM, Sylvain C, Woo TM, Yang J (2009) Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047). J Med Chem 52(9):3028–3038

    PubMed  CAS  Google Scholar 

  68. Chauhan D, Singh AV, Aujay M, Kirk CJ, Bandi M, Ciccarelli B, Raje N, Richardson P, Anderson KC (2010) A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma. Blood 116(23):4906–4915

    PubMed  CAS  PubMed Central  Google Scholar 

  69. Ciechanover A (2005) Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat Rev Mol Cell Biol 6(1):79–87

    PubMed  CAS  Google Scholar 

  70. Ghosh S, Karin M (2002) Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl):S81–96

    PubMed  CAS  Google Scholar 

  71. Ghosh S, Baltimore D (1990) Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B. Nature 344(6267):678–682

    PubMed  CAS  Google Scholar 

  72. Traenckner EB, Pahl HL, Henkel T, Schmidt KN, Wilk S, Baeuerle PA (1995) Phosphorylation of human I kappa B-alpha on serines 32 and 36 controls I kappa B-alpha proteolysis and NF-kappa B activation in response to diverse stimuli. EMBO J 14(12):2876–2883

    PubMed  CAS  PubMed Central  Google Scholar 

  73. Aggarwal BB (2004) Nuclear factor-kappaB: the enemy within. Cancer Cell 6(3):203–208

    PubMed  CAS  Google Scholar 

  74. Van Waes C (2007) Nuclear factor-kappaB in development, prevention, and therapy of cancer. Clin Cancer Res 13(4):1076–1082

    PubMed  Google Scholar 

  75. Ondrey FG, Dong G, Sunwoo J, Chen Z, Wolf JS, Crowl-Bancroft CV, Mukaida N, Van Waes C (1999) Constitutive activation of transcription factors NF-(kappa)B, AP-1, and NF-IL6 in human head and neck squamous cell carcinoma cell lines that express pro-inflammatory and pro-angiogenic cytokines. Mol Carcinog 26(2):119–129

    PubMed  CAS  Google Scholar 

  76. Allen CT, Ricker JL, Chen Z, Van Waes C (2007) Role of activated nuclear factor-kappaB in the pathogenesis and therapy of squamous cell carcinoma of the head and neck. Head Neck 29(10):959–971

    PubMed  Google Scholar 

  77. Druzgal CH, Chen Z, Yeh NT, Thomas GR, Ondrey FG, Duffey DC, Vilela RJ, Ende K, McCullagh L, Rudy SF, Muir C, Herscher LL, Morris JC, Albert PS, Van Waes C (2005) A pilot study of longitudinal serum cytokine and angiogenesis factor levels as markers of therapeutic response and survival in patients with head and neck squamous cell carcinoma. Head Neck 27(9):771–784

    PubMed  Google Scholar 

  78. Zhang PL, Pellitteri PK, Law A, Gilroy PA, Wood GC, Kennedy TL, Blasick TM, Lun M, Schuerch C 3rd, Brown RE (2005) Overexpression of phosphorylated nuclear factor-kappa B in tonsillar squamous cell carcinoma and high-grade dysplasia is associated with poor prognosis. Mod Pathol 18(7):924–932

    PubMed  CAS  Google Scholar 

  79. Chung CH, Parker JS, Ely K, Carter J, Yi Y, Murphy BA, Ang KK, El-Naggar AK, Zanation AM, Cmelak AJ, Levy S, Slebos RJ, Yarbrough WG (2006) Gene expression profiles identify epithelial-to-mesenchymal transition and activation of nuclear factor-kappaB signaling as characteristics of a high-risk head and neck squamous cell carcinoma. Cancer Res 66(16):8210–8218

    PubMed  CAS  Google Scholar 

  80. Allen C, Duffy S, Teknos T, Islam M, Chen Z, Albert PS, Wolf G, Van Waes C (2007) Nuclear factor-kappaB-related serum factors as longitudinal biomarkers of response and survival in advanced oropharyngeal carcinoma. Clin Cancer Res 13(11):3182–3190

    PubMed  CAS  Google Scholar 

  81. Traenckner EB, Wilk S, Baeuerle PA (1994) A proteasome inhibitor prevents activation of NF-kappa B and stabilizes a newly phosphorylated form of I kappa B-alpha that is still bound to NF-kappa B. EMBO J 13(22):5433–5441

    PubMed  CAS  PubMed Central  Google Scholar 

  82. Van Waes C, Chang AA, Lebowitz PF, Druzgal CH, Chen Z, Elsayed YA, Sunwoo JB, Rudy SF, Morris JC, Mitchell JB, Camphausen K, Gius D, Adams J, Sausville EA, Conley BA (2005) Inhibition of nuclear factor-kappaB and target genes during combined therapy with proteasome inhibitor bortezomib and reirradiation in patients with recurrent head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 63(5):1400–1412

    PubMed  Google Scholar 

  83. Allen C, Saigal K, Nottingham L, Arun P, Chen Z, Van Waes C (2008) Bortezomib-induced apoptosis with limited clinical response is accompanied by inhibition of canonical but not alternative nuclear factor-{kappa}B subunits in head and neck cancer. Clin Cancer Res 14(13):4175–4185

    PubMed  CAS  Google Scholar 

  84. Fribley AM, Evenchik B, Zeng Q, Park BK, Guan JY, Zhang H, Hale TJ, Soengas MS, Kaufman RJ, Wang CY (2006) Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa. J Biol Chem 281(42):31440–31447

    PubMed  CAS  Google Scholar 

  85. Yang Y, Ikezoe T, Saito T, Kobayashi M, Koeffler HP, Taguchi H (2004) Proteasome inhibitor PS-341 induces growth arrest and apoptosis of non-small cell lung cancer cells via the JNK/c-Jun/AP-1 signaling. Cancer Sci 95(2):176–180

    PubMed  CAS  Google Scholar 

  86. Dai Y, Rahmani M, Pei XY, Dent P, Grant S (2004) Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms. Blood 104(2):509–518

    PubMed  CAS  Google Scholar 

  87. Wagenblast J, Hambek M, Baghi M, Gstottner W, Strebhardt K, Ackermann H, Knecht R (2008) Antiproliferative activity of bortezomib alone and in combination with cisplatin or docetaxel in head and neck squamous cell carcinoma cell lines. J Cancer Res Clin Oncol 134(3):323–330

    PubMed  CAS  Google Scholar 

  88. Weber CN, Cerniglia GJ, Maity A, Gupta AK (2007) Bortezomib sensitizes human head and neck carcinoma cells SQ20B to radiation. Cancer Biol Ther 6(2):156–159

    PubMed  CAS  Google Scholar 

  89. Tamatani T, Takamaru N, Hara K, Kinouchi M, Kuribayashi N, Ohe G, Uchida D, Fujisawa K, Nagai H, Miyamoto Y (2013) Bortezomib-enhanced radiosensitization through the suppression of radiation-induced nuclear factor-kappaB activity in human oral cancer cells. Int J Oncol 42(3):935–944

    PubMed  CAS  Google Scholar 

  90. Li C, Zang Y, Sen M, Leeman-Neill RJ, Man DS, Grandis JR, Johnson DE (2009) Bortezomib up-regulates activated signal transducer and activator of transcription-3 and synergizes with inhibitors of signal transducer and activator of transcription-3 to promote head and neck squamous cell carcinoma cell death. Mol Cancer Ther 8(8):2211–2220

    PubMed  CAS  PubMed Central  Google Scholar 

  91. Li C, Johnson DE (2012) Bortezomib induces autophagy in head and neck squamous cell carcinoma cells via JNK activation. Cancer Lett 314(1):102–107

    PubMed  CAS  PubMed Central  Google Scholar 

  92. Grandis JR, Tweardy DJ (1993) 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 53(15):3579–3584

    PubMed  CAS  Google Scholar 

  93. Fung C, Grandis JR (2010) Emerging drugs to treat squamous cell carcinomas of the head and neck. Expert Opin Emerg Drugs 15(3):355–373

    PubMed  CAS  PubMed Central  Google Scholar 

  94. Rubin Grandis J, Zeng Q, Tweardy DJ (1996) Retinoic acid normalizes the increased gene transcription rate of TGF-alpha and EGFR in head and neck cancer cell lines. Nat Med 2(2):237–240

    PubMed  CAS  Google Scholar 

  95. Sheu JJ, Hua CH, Wan L, Lin YJ, Lai MT, Tseng HC, Jinawath N, Tsai MH, Chang NW, Lin CF, Lin CC, Hsieh LJ, Wang TL, Shih Ie M, Tsai FJ (2009) Functional genomic analysis identified epidermal growth factor receptor activation as the most common genetic event in oral squamous cell carcinoma. Cancer Res 69(6):2568–2576. doi:10.1158/0008-5472.CAN-08-3199

    PubMed  CAS  Google Scholar 

  96. Rubin Grandis J, Melhem MF, Gooding WE, Day R, Holst VA, Wagener MM, Drenning SD, Tweardy DJ (1998) Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 90(11):824–832

    PubMed  CAS  Google Scholar 

  97. Rivera F, Garcia-Castano A, Vega N, Vega-Villegas ME, Gutierrez-Sanz L (2009) Cetuximab in metastatic or recurrent head and neck cancer: the EXTREME trial. Expert Rev Anticancer Ther 9(10):1421–1428

    PubMed  CAS  Google Scholar 

  98. Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK (2010) Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 11(1):21–28. doi:10.1016/S1470-2045(09)70311-0

    PubMed  CAS  Google Scholar 

  99. Wagenblast J, Baghi M, Arnoldner C, Bisdas S, Gstottner W, Ackermann H, May A, Knecht R, Hambek M (2008) Effect of bortezomib and cetuximab in EGF-stimulated HNSCC. Anticancer Res 28(4B):2239–2243

    PubMed  CAS  Google Scholar 

  100. Wagenblast J, Baghi M, Arnoldner C, Bisdas S, Gstottner W, Ackermann H, May A, Hambek M, Knecht R (2009) Cetuximab enhances the efficacy of bortezomib in squamous cell carcinoma cell lines. J Cancer Res Clin Oncol 135(3):387–393

    PubMed  CAS  Google Scholar 

  101. Argiris A, Duffy AG, Kummar S, Simone NL, Arai Y, Kim SW, Rudy SF, Kannabiran VR, Yang X, Jang M, Chen Z, Suksta N, Cooley-Zgela T, Ramanand SG, Ahsan A, Nyati MK, Wright JJ, Van Waes C (2011) Early tumor progression associated with enhanced EGFR signaling with bortezomib, cetuximab, and radiotherapy for head and neck cancer. Clin Cancer Res 17(17):5755–5764

    PubMed  CAS  PubMed Central  Google Scholar 

  102. Yoshiba S, Iwase M, Kurihara S, Uchida M, Kurihara Y, Watanabe H, Shintani S (2011) Proteasome inhibitor sensitizes oral squamous cell carcinoma cells to TRAIL-mediated apoptosis. Oncol Rep 25(3):645–652

    PubMed  CAS  Google Scholar 

  103. Seki N, Toh U, Sayers TJ, Fujii T, Miyagi M, Akagi Y, Kusukawa J, Kage M, Shirouzu K, Yamana H (2010) Bortezomib sensitizes human esophageal squamous cell carcinoma cells to TRAIL-mediated apoptosis via activation of both extrinsic and intrinsic apoptosis pathways. Mol Cancer Ther 9(6):1842–1851

    PubMed  CAS  PubMed Central  Google Scholar 

  104. Kim J, Guan J, Chang I, Chen X, Han D, Wang CY (2010) PS-341 and histone deacetylase inhibitor synergistically induce apoptosis in head and neck squamous cell carcinoma cells. Mol Cancer Ther 9(7):1977–1984

    PubMed  CAS  PubMed Central  Google Scholar 

  105. Duan J, Friedman J, Nottingham L, Chen Z, Ara G, Van Waes C (2007) Nuclear factor-kappaB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101. Mol Cancer Ther 6(1):37–50

    PubMed  CAS  Google Scholar 

  106. Wagenblast J, Baghi M, Arnoldner C, Bisdas S, Gstottner W, May A, Knecht R, Hambek M (2008) Effects of combination treatment of bortezomib and dexamethasone in SCCHN cell lines depend on tumor cell specificity. Oncol Rep 20(5):1207–1211

    PubMed  CAS  Google Scholar 

  107. Leinung M, Hirth D, Tahtali A, Diensthuber M, Stover T, Wagenblast J (2012) Fighting cancer from different signalling pathways: Effects of the proteasome inhibitor Bortezomib in combination with the polo-like-kinase-1-inhibitor BI2536 in SCCHN. Oncol Lett 4(6):1305–1308

    PubMed  CAS  PubMed Central  Google Scholar 

  108. Gilbert J, Lee JW, Argiris A, Haigentz M Jr, Feldman LE, Jang M, Arun P, Van Waes C, Forastiere AA (2013) Phase II 2-arm trial of the proteasome inhibitor, PS-341 (bortezomib) in combination with irinotecan or PS-341 alone followed by the addition of irinotecan at time of progression in patients with locally recurrent or metastatic squamous cell carcinoma of the head and neck (E1304): a trial of the Eastern Cooperative Oncology Group. Head Neck 35(7):942–948

    PubMed  PubMed Central  Google Scholar 

  109. Pugh TJ, Chen C, Rabinovitch R, Eckhardt SG, Rusthoven KE, Swing R, Raben D (2010) Phase I trial of bortezomib and concurrent external beam radiation in patients with advanced solid malignancies. Int J Radiat Oncol Biol Phys 78(2):521–526

    PubMed  CAS  Google Scholar 

  110. Kubicek GJ, Axelrod RS, Machtay M, Ahn PH, Anne PR, Fogh S, Cognetti D, Myers TJ, Curran WJ Jr, Dicker AP (2012) Phase I trial using the proteasome inhibitor bortezomib and concurrent chemoradiotherapy for head-and-neck malignancies. Int J Radiat Oncol Biol Phys 83(4):1192–1197

    PubMed  CAS  Google Scholar 

  111. Chung CH, Aulino J, Muldowney NJ, Hatakeyama H, Baumann J, Burkey B, Netterville J, Sinard R, Yarbrough WG, Cmelak AJ, Slebos RJ, Shyr Y, Parker J, Gilbert J, Murphy BA (2010) Nuclear factor-kappa B pathway and response in a phase II trial of bortezomib and docetaxel in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol 21(4):864–870

    PubMed  CAS  PubMed Central  Google Scholar 

  112. An J, Rettig MB (2007) Epidermal growth factor receptor inhibition sensitizes renal cell carcinoma cells to the cytotoxic effects of bortezomib. Mol Cancer Ther 6(1):61–69

    PubMed  CAS  Google Scholar 

  113. Dudek AZ, Lesniewski-Kmak K, Shehadeh NJ, Pandey ON, Franklin M, Kratzke RA, Greeno EW, Kumar P (2009) Phase I study of bortezomib and cetuximab in patients with solid tumours expressing epidermal growth factor receptor. Br J Cancer 100(9):1379–1384

    PubMed  CAS  PubMed Central  Google Scholar 

  114. Mork J, Lie AK, Glattre E, Hallmans G, Jellum E, Koskela P, Moller B, Pukkala E, Schiller JT, Youngman L, Lehtinen M, Dillner J (2001) Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 344(15):1125–1131

    PubMed  CAS  Google Scholar 

  115. Herrero R, Castellsague X, Pawlita M, Lissowska J, Kee F, Balaram P, Rajkumar T, Sridhar H, Rose B, Pintos J, Fernandez L, Idris A, Sanchez MJ, Nieto A, Talamini R, Tavani A, Bosch FX, Reidel U, Snijders PJ, Meijer CJ, Viscidi R, Munoz N, Franceschi S (2003) Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 95(23):1772–1783

    PubMed  Google Scholar 

  116. Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L, Zahurak ML, Daniel RW, Viglione M, Symer DE, Shah KV, Sidransky D (2000) Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 92(9):709–720

    PubMed  CAS  Google Scholar 

  117. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML (2008) Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol 26(4):612–619

    PubMed  Google Scholar 

  118. Nasman A, Attner P, Hammarstedt L, Du J, Eriksson M, Giraud G, Ahrlund-Richter S, Marklund L, Romanitan M, Lindquist D, Ramqvist T, Lindholm J, Sparen P, Ye W, Dahlstrand H, Munck-Wikland E, Dalianis T (2009) Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 125(2):362–366

    PubMed  Google Scholar 

  119. Gillison ML (2004) Human papillomavirus-associated head and neck cancer is a distinct epidemiologic, clinical, and molecular entity. Semin Oncol 31(6):744–754

    PubMed  Google Scholar 

  120. Lindel K, Beer KT, Laissue J, Greiner RH, Aebersold DM (2001) Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma. Cancer 92(4):805–813

    PubMed  CAS  Google Scholar 

  121. Li W, Thompson CH, O'Brien CJ, McNeil EB, Scolyer RA, Cossart YE, Veness MJ, Walker DM, Morgan GJ, Rose BR (2003) Human papillomavirus positivity predicts favourable outcome for squamous carcinoma of the tonsil. Int J Cancer 106(4):553–558

    PubMed  CAS  Google Scholar 

  122. Weinberger PM, Yu Z, Haffty BG, Kowalski D, Harigopal M, Brandsma J, Sasaki C, Joe J, Camp RL, Rimm DL, Psyrri A (2006) Molecular classification identifies a subset of human papillomavirus-associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 24(5):736–747

    PubMed  CAS  Google Scholar 

  123. Licitra L, Perrone F, Bossi P, Suardi S, Mariani L, Artusi R, Oggionni M, Rossini C, Cantu G, Squadrelli M, Quattrone P, Locati LD, Bergamini C, Olmi P, Pierotti MA, Pilotti S (2006) High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 24(36):5630–5636

    PubMed  CAS  Google Scholar 

  124. Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, Forastiere A, Gillison ML (2008) Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100(4):261–269

    PubMed  CAS  Google Scholar 

  125. Gillison ML, D'Souza G, Westra W, Sugar E, Xiao W, Begum S, Viscidi R (2008) Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst 100(6):407–420

    PubMed  Google Scholar 

  126. Psyrri A, Gouveris P, Vermorken JB (2009) Human papillomavirus-related head and neck tumors: clinical and research implication. Curr Opin Oncol 21(3):201–205

    PubMed  Google Scholar 

  127. Balz V, Scheckenbach K, Gotte K, Bockmuhl U, Petersen I, Bier H (2003) Is the p53 inactivation frequency in squamous cell carcinomas of the head and neck underestimated? Analysis of p53 exons 2-11 and human papillomavirus 16/18 E6 transcripts in 123 unselected tumor specimens. Cancer Res 63(6):1188–1191

    PubMed  CAS  Google Scholar 

  128. Poeta ML, Manola J, Goldwasser MA, Forastiere A, Benoit N, Califano JA, Ridge JA, Goodwin J, Kenady D, Saunders J, Westra W, Sidransky D, Koch WM (2007) TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med 357(25):2552–2561

    PubMed  CAS  PubMed Central  Google Scholar 

  129. Westra WH, Taube JM, Poeta ML, Begum S, Sidransky D, Koch WM (2008) Inverse relationship between human papillomavirus-16 infection and disruptive p53 gene mutations in squamous cell carcinoma of the head and neck. Clin Cancer Res 14(2):366–369

    PubMed  CAS  Google Scholar 

  130. Scheffner M, Huibregtse JM, Vierstra RD, Howley PM (1993) The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75(3):495–505

    PubMed  CAS  Google Scholar 

  131. Munger K, Basile JR, Duensing S, Eichten A, Gonzalez SL, Grace M, Zacny VL (2001) Biological activities and molecular targets of the human papillomavirus E7 oncoprotein. Oncogene 20(54):7888–7898

    PubMed  CAS  Google Scholar 

  132. Ferris RL, Martinez I, Sirianni N, Wang J, Lopez-Albaitero A, Gollin SM, Johnson JT, Khan S (2005) Human papillomavirus-16 associated squamous cell carcinoma of the head and neck (SCCHN): a natural disease model provides insights into viral carcinogenesis. Eur J Cancer 41(5):807–815

    PubMed  CAS  Google Scholar 

  133. Rampias T, Sasaki C, Weinberger P, Psyrri A (2009) E6 and e7 gene silencing and transformed phenotype of human papillomavirus 16-positive oropharyngeal cancer cells. J Natl Cancer Inst 101(6):412–423

    PubMed  CAS  Google Scholar 

  134. Kimple RJ, Smith MA, Blitzer GC, Torres AD, Martin JA, Yang RZ, Peet CR, Lorenz LD, Nickel KP, Klingelhutz AJ, Lambert PF, Harari PM (2013) Enhanced Radiation Sensitivity in HPV-Positive Head and Neck Cancer. Cancer Res 73(15):4791–4800

    PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgements

We apologize to those authors whose work we have been unable to cite. This work was supported by National Institutes of Health grants R01 CA137260 and P50 CA097190.

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Authors and Affiliations

  1. Department of Otolaryngology, University of Pittsburgh School of Medicine, Eye & Ear Building, Suite 500, 200 Lothrop Street, Pittsburgh, PA, 15213, USA

    Jason I. Kass

  2. Departments of Otolaryngology and Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, and The University of Pittsburgh Cancer Institute, Eye & Ear Building, Suite 500, 200 Lothrop Street, Pittsburgh, PA, 15213, USA

    Jennifer R. Grandis

  3. Departments of Medicine and Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, and The University of Pittsburgh Cancer Institute, Hillman Cancer Center, Room 2.18c, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA

    Daniel E. Johnson

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  1. Jason I. Kass
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  2. Jennifer R. Grandis
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Correspondence to Daniel E. Johnson .

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  1. Wayne State University, Detroit, Michigan, USA

    Q. Ping Dou

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Kass, J.I., Grandis, J.R., Johnson, D.E. (2014). Overcoming Inherent Resistance to Proteasome Inhibitors in Head and Neck Cancer: Challenges and New Approaches. In: Dou, Q. (eds) Resistance to Proteasome Inhibitors in Cancer. Resistance to Targeted Anti-Cancer Therapeutics. Springer, Cham. https://doi.org/10.1007/978-3-319-06752-0_8

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