Skip to main content

Targeted therapies for non-HPV-related head and neck cancer: challenges and opportunities in the context of predictive, preventive, and personalized medicine

Abstract

Head and neck squamous cell carcinoma (HNSCC) develops in the mucosal lining of the upper aerodigestive tract, principally as a result of exposure to carcinogens present in tobacco products and alcohol, with oncogenic papillomaviruses also being recognized as etiological agents in a limited proportion of cases. As such, there is considerable scope for prevention of disease development and progression. However, despite multimodal approaches to treatment, tumor recurrence and metastatic disease are common problems, and clinical outcome is unsatisfactory. As our understanding of the genetics and biochemical aberrations in HNSCC has improved, so the development and use of molecularly targeted drugs to combat the disease have come to the fore. In this article, we review molecular mechanisms that alter signal transduction downstream of the epidermal growth factor receptor (EGFR) as well as those that perturb orderly cell cycle progression, such as p53 mutation, cyclin overexpression, and loss of cyclin-dependent kinase inhibitor function. We outline some of the tactics that have been employed to combat the altered biochemistry. These include blockade of the EGFR using humanized monoclonal antibodies such as cetuximab and small molecule tyrosine kinase inhibitors (TKIs) such as erlotinib/gefitinib and subsequent generations of TKIs, restoration of p53 function using MIRA compounds, and inhibition of cyclin-dependent kinase and aurora kinase activity using drugs such as palbociclib and alisertib. Knowledge of the underlying molecular mechanisms may be utilizable in order to predict disease behavior and tailor therapeutic interventions in a more personalized approach to improve clinical response. Use of liquid biopsy, omics platforms, and salivary diagnostics hold promise in this regard.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. Vigneswaran N, Williams MD. Epidemiologic trends in head and neck cancer and aids in diagnosis. Oral Maxillofac Surg Clin North Am. 2014;26(2):123–41.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Price KA, Cohen EE. Current treatment options for metastatic head and neck cancer. Curr Treat Options Oncol. 2012;13(1):35–46.

    Article  PubMed  Google Scholar 

  3. Sacco AG, Cohen EE. Current treatment options for recurrent or metastatic head and neck squamous cell carcinoma. J Clin Oncol. 2015;33(29):3305–13.

    Article  CAS  PubMed  Google Scholar 

  4. Carpenter G, Cohen S. Epidermal growth factor. Annu Rev Biochem. 1979;48:193–216.

    Article  CAS  PubMed  Google Scholar 

  5. Rubin Grandis J, Zeng Q, Drenning SD. Epidermal growth factor receptor--mediated stat3 signaling blocks apoptosis in head and neck cancer. Laryngoscope. 2000;110(5 Pt 1):868–74.

    Article  CAS  PubMed  Google Scholar 

  6. Grandis JR, Drenning SD, Chakraborty A, Zhou MY, Zeng Q, Pitt AS, et al. Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor- mediated cell growth in vitro. J Clin Invest. 1998;102(7):1385–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Buday L, Downward J. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell. 1993;73(3):611–20.

    Article  CAS  PubMed  Google Scholar 

  8. Chen P, Gupta K, Wells A. Cell movement elicited by epidermal growth factor receptor requires kinase and autophosphorylation but is separable from mitogenesis. J Cell Biol. 1994;124(4):547–55.

    Article  CAS  PubMed  Google Scholar 

  9. Seiwert TY, Cohen EE. State-of-the-art management of locally advanced head and neck cancer. Br J Cancer. 2005;92(8):1341–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Psyrri A, Yu Z, Weinberger PM, Sasaki C, Haffty B, Camp R, et al. Quantitative determination of nuclear and cytoplasmic epidermal growth factor receptor expression in oropharyngeal squamous cell cancer by using automated quantitative analysis. Clin Cancer Res. 2005;11(16):5856–62.

    Article  CAS  PubMed  Google Scholar 

  11. 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.

    Article  CAS  PubMed  Google Scholar 

  12. Miyaguchi M, Olofsson J, Hellquist HB. Expression of epidermal growth factor receptor in laryngeal dysplasia and carcinoma. Acta Otolaryngol. 1990;110(3–4):309–13.

    Article  CAS  PubMed  Google Scholar 

  13. Nagalakshmi K, Jamil K, Pingali U, Reddy MV, Attili SSV. Epidermal growth factor receptor (EGFR) mutations as biomarker for head and neck squamous cell carcinomas (HNSCC). Biomarkers. 2014;19(3):198–206.

    Article  CAS  PubMed  Google Scholar 

  14. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39.

    Article  CAS  PubMed  Google Scholar 

  15. Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–500.

  16. Takano T, Ohe Y, Sakamoto H, Tsuta K, Matsuno Y, Tateishi U, et al. Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol. 2005;23(28):6829–37.

    Article  CAS  PubMed  Google Scholar 

  17. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101(36):13306–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lee JW, Soung YH, Kim SY, Nam HK, Park WS, Nam SW, et al. Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clin Cancer Res. 2005;11(8):2879–82.

    Article  CAS  PubMed  Google Scholar 

  19. Frame MC. Newest findings on the oldest oncogene; how activated src does it. J Cell Sci. 2004;117(Pt 7):989–98.

    Article  CAS  PubMed  Google Scholar 

  20. Summy JM, Gallick GE. Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev. 2003;22(4):337–58.

    Article  CAS  PubMed  Google Scholar 

  21. Scaltriti M, Baselga J. The epidermal growth factor receptor pathway: a model for targeted therapy. Clin Cancer Res. 2006;12(18):5268–72.

    Article  CAS  PubMed  Google Scholar 

  22. Cunningham DL, Creese AJ, Auciello G, Sweet SMM, Tatar T, Rappoport JZ, et al. Novel binding partners and differentially regulated phosphorylation sites clarify Eps8 as a multi-functional adaptor. PLoS One. 2013;8(4):e61513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Maa MC, Leu TH, McCarley DJ, Schatzman RC, Parsons SJ. Potentiation of epidermal growth factor receptor-mediated oncogenesis by c-Src: implications for the etiology of multiple human cancers. Proc Natl Acad Sci U S A. 1995;92(15):6981–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, 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.

    Article  CAS  PubMed  Google Scholar 

  25. Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA, Eastern Cooperative Oncology Group. 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. 2005;23(34):8646–54.

    Article  PubMed  Google Scholar 

  26. Sacco AG, Messer K, Natsuhara A, Chen R, Wong DJL, Wordenet FP et al. An open-label, non-randomized, multi-arm, phase II trial evaluating pembrolizumab combined with cetuximab in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): Results of the interim safety analysis. J Clin Oncol. 2018;36(15_suppl):6037.

    Article  Google Scholar 

  27. Ang KK, Zhang Q, Rosenthal DI, Nguyen-Tan PF, Sherman EJ, Weber RS, et al. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol. 2014;32(27):2940–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–78.

    Article  CAS  PubMed  Google Scholar 

  29. Bozec A, Sudaka A, Toussan N, Fischel JL, Etienne-Grimaldi MC, Milano G. Combination of sunitinib, cetuximab and irradiation in an orthotopic head and neck cancer model. Ann Oncol. 2009;20(10):1703–7.

    Article  CAS  PubMed  Google Scholar 

  30. Tong CC, Ko EC, Sung MW, Cesaretti JA, Stock RG, Packer SH, et al. Phase II trial of concurrent sunitinib and image-guided radiotherapy for oligometastases. PLoS One. 2012;7(6):e36979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Michel L, Ley J, Wildes TM, Schaffer A, Robinson A, Chun SE, et al. Phase I trial of palbociclib, a selective cyclin dependent kinase 4/6 inhibitor, in combination with cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma. Oral Oncol. 2016;58:41–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Argiris A, Kotsakis AP, Hoang T, Worden FP, Savvides P, Gibson MK, et al. Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck. Ann Oncol. 2013;24(1):220–5.

    Article  CAS  PubMed  Google Scholar 

  33. Massarelli E, Lin H, Ginsberg LE, Tran HT, Lee JJ, Canales JR, et al. Phase II trial of everolimus and erlotinib in patients with platinum-resistant recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol. 2015;26(7):1476–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stewart JS, Cohen EE, Licitra L, Van Herpen CM, Khorprasert C, Soulieres D, et al. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol. 2009;27(11):1864–71.

  35. Seiwert TY, Fayette J, Cupissol D, del Campo JM, Clement PM, Hitt R, et al. A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck. Ann Oncol. 2014;25(9):1813–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Vermorken JB, et al. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol. 2015;16(5):583–94.

    Article  CAS  PubMed  Google Scholar 

  37. Lamb YN, Scott LJ. Osimertinib: areview in T790M-positive advanced non-small cell lung Cancer. Target Oncol. 2017;12(4):555–62.

    Article  PubMed  Google Scholar 

  38. Le X, et al. Landscape of EGFR-dependent and -independent resistance mechanisms to Osimertinib and continuation therapy beyond progression in EGFR-mutant NSCLC. Clin Cancer Res. 2018;24(24):6195–203.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012;11(2):317–28.

    Article  CAS  PubMed  Google Scholar 

  40. Soulieres D, Faivre S, Mesía R, Remenár É, Li SH, Karpenko A, et al. Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncol. 2017;18(3):323–35.

  41. Liu N, Rowley BR, Bull CO, Schneider C, Haegebarth A, Schatz CA, et al. BAY 80-6946 is a highly selective intravenous PI3K inhibitor with potent p110alpha and p110delta activities in tumor cell lines and xenograft models. Mol Cancer Ther. 2013;12(11):2319–30.

    Article  CAS  PubMed  Google Scholar 

  42. Doi T, Fuse N, Yoshino T, Kojima T, Bando H, Miyamoto H, et al. A phase I study of intravenous PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors. Cancer Chemother Pharmacol. 2017;79(1):89–98.

    Article  CAS  PubMed  Google Scholar 

  43. Liu X, Kambrick S, Fu S, Naing A, Subbiah V, Blumenschein GR, et al. Advanced malignancies treated with a combination of the VEGF inhibitor bevacizumab, anti-EGFR antibody cetuximab, and the mTOR inhibitor temsirolimus. Oncotarget. 2016;7(17):23227–38.

  44. Saba NF, Hurwitz SJ, Magliocca K, Kim S, Owonikoko TK, Harvey D, et al. Phase 1 and pharmacokinetic study of everolimus in combination with cetuximab and carboplatin for recurrent/metastatic squamous cell carcinoma of the head and neck. Cancer. 2014;120(24):3940–51.

    Article  CAS  PubMed  Google Scholar 

  45. Johnson FM, Saigal B, Talpaz M, Donato NJ. Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells. Clin Cancer Res. 2005;11(19 Pt 1):6924–32. 

  46. Brooks HD, Glisson BS, Bekele BN, Johnson FM, Ginsberg LE, el-Naggar A, et al. Phase 2 study of dasatinib in the treatment of head and neck squamous cell carcinoma. Cancer. 2011;117(10):2112–9.

    Article  CAS  PubMed  Google Scholar 

  47. Bauman JE, Duvvuri U, Gooding WE, Rath TJ, Gross ND, Song J, et al. Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer. JCI Insight. 2017;2(6):e90449.

  48. Fury MG, Baxi S, Shen R, Kelly KW, Lipson BL, Carlson D, et al. Phase II study of saracatinib (AZD0530) for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Anticancer Res. 2011;31(1):249–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Fletcher GC, Brokx RD, Denny TA, Hembrough TA, Plum SM, Fogler WE, et al. ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action. Mol Cancer Ther. 2011;10(1):126–37.

    Article  CAS  PubMed  Google Scholar 

  50. Yang J, Ikezoe T, Nishioka C, Tasaka T, Taniguchi A, Kuwayama Y, et al. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood. 2007;110(6):2034–40.

    Article  CAS  PubMed  Google Scholar 

  51. Payton M, Cheung HK, Ninniri MSS, Marinaccio C, Wayne WC, Hanestad K, et al. Dual targeting of Aurora kinases with AMG 900 exhibits potent preclinical activity against acute myeloid leukemia with distinct post-mitotic outcomes. Mol Cancer Ther. 2018;17(12):2575–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Graff JN, Higano CS, Hahn NM, Taylor MH, Zhang B, Zhou X, et al. Open-label, multicenter, phase 1 study of alisertib (MLN8237), an aurora a kinase inhibitor, with docetaxel in patients with solid tumors. Cancer. 2016;122(16):2524–33.

    Article  CAS  PubMed  Google Scholar 

  53. Falchook G, Kurzrock R, Gouw L, Hong D, McGregor KA, Zhou X, et al. Investigational Aurora a kinase inhibitor alisertib (MLN8237) as an enteric-coated tablet formulation in non-hematologic malignancies: phase 1 dose-escalation study. Investig New Drugs. 2014;32(6):1181–7.

    Article  CAS  Google Scholar 

  54. Lee P, Alvarez RH, Melichar B, Adenis A, Bennouna J, Schusterbauer C, et al. Phase I/II study of the investigational aurora A kinase (AAK) inhibitor MLN8237 (alisertib) in patients (pts) with non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), breast cancer (BrC), head/neck cancer (H&N), and gastroesophageal (GE) adenocarcinoma: Preliminary phase II results. J Clin Oncol. 2012;30(15_suppl):3010.

  55. Melichar B, Adenis A, Lockhart AC, Bennouna J, Dees EC, Kayaleh O, et al. Safety and activity of alisertib, an investigational aurora kinase a inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol. 2015;16(4):395–405.

    Article  CAS  PubMed  Google Scholar 

  56. Stephenson JJ, Nemunaitis J, Joy AA, Martin JC, Jou YM, Zhang D, et al. Randomized phase 2 study of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus erlotinib in patients with non-small cell lung cancer. Lung Cancer. 2014;83(2):219–23.

    Article  PubMed  Google Scholar 

  57. Mita MM, Mita AC, Moseley JL, Poon J, Small KA, Jou YM, et al. Phase 1 safety, pharmacokinetic and pharmacodynamic study of the cyclin-dependent kinase inhibitor dinaciclib administered every three weeks in patients with advanced malignancies. Br J Cancer. 2017;117:1258–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Adkins D, Oppelt PJ, Ley JC, Trinkaus K, Neupane PC, Saccoet AG, et al. Multicenter phase II trial of palbociclib, a selective cyclin dependent kinase (CDK) 4/6 inhibitor, and cetuximab in platinum-resistant HPV unrelated (−) recurrent/metastatic head and neck squamous cell carcinoma (RM HNSCC). J Clin Oncol. 2018;36(15_suppl):6008.

  59. Wischhusen J, Naumann U, Ohgaki H, Rastinejad F, Weller M. CP-31398, a novel p53-stabilizing agent, induces p53-dependent and p53-independent glioma cell death. Oncogene. 2003;22(51):8233–45.

    Article  CAS  PubMed  Google Scholar 

  60. Tang X, Zhu Y, Han L, Kim AL, Kopelovich L, Bickers DR, et al. CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice. J Clin Invest. 2007;117(12):3753–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Foster BA, Coffey HA, Morin MJ, Rastinejad F. Pharmacological rescue of mutant p53 conformation and function. Science. 1999;286(5449):2507–10.

    Article  CAS  PubMed  Google Scholar 

  62. Parrales A, Iwakuma T. Targeting oncogenic mutant p53 for Cancer therapy. Front Oncol. 2015;5:288.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Chen F, Wang W, El-Deiry WS. Current strategies to target p53 in cancer. Biochem Pharmacol. 2010;80(5):724–30.

    Article  CAS  PubMed  Google Scholar 

  64. Bykov VJ, Issaeva N, Zache N, Shilov A, Hultcrantz M, Bergman J, et al. Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs. J Biol Chem. 2005;280(34):30384–91.

  65. Saha MN, Chen Y, Chen MH, Chen G, Chang H. Small molecule MIRA-1 induces in vitro and in vivo anti-myeloma activity and synergizes with current anti-myeloma agents. Br J Cancer. 2014;110(9):2224–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Schuler PJ, Harasymczuk M, Visus C, DeLeo A, Trivedi S, Lei Y, et al. Phase I dendritic cell p53 peptide vaccine for head and neck cancer. Clin Cancer Res. 2014;20(9):2433–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LGGC, Masucci M, et al. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med. 2004;10(12):1321–8.

    Article  CAS  PubMed  Google Scholar 

  68. Roh JL, Ko JH, Moon SJ, Ryu CH, Choi JY, Koch WM. The p53-reactivating small-molecule RITA enhances cisplatin-induced cytotoxicity and apoptosis in head and neck cancer. Cancer Lett. 2012;325(1):35–41.

    Article  CAS  PubMed  Google Scholar 

  69. Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65(7):2554–9.

    Article  CAS  PubMed  Google Scholar 

  70. Lui VW, Hedberg ML, Li H, Vangara BS, Pendleton K, Zeng Y, et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov. 2013;3(7):761–9.

  71. Seiwert TY, Zuo Z, Keck MK, Khattri A, Pedamallu CS, Stricker T, et al. Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin Cancer Res. 2015;21(3):632–41.

    Article  CAS  PubMed  Google Scholar 

  72. Isaacsson Velho PH, Castro G Jr, Chung CH. Targeting the PI3K Pathway in Head and Neck Squamous Cell Carcinoma. Am Soc Clin Oncol Educ Book. 2015;35:123–8.

    Article  Google Scholar 

  73. Qiu W, Schönleben F, Li X, Ho DJ, Close LG, Manolidis S, et al. PIK3CA mutations in head and neck squamous cell carcinoma. Clin Cancer Res. 2006;12(5):1441–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Du L, Shen J, Weems A, Lu SL. Role of phosphatidylinositol-3-kinase pathway in head and neck squamous cell carcinoma. J Oncol. 2012;2012:450179. 

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Perez-Tenorio G, Alkhori L, Olsson B, Waltersson MA, Nordenskjold B, Rutqvist LE, et al. PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res. 2007;13(12):3577–84.

    Article  CAS  PubMed  Google Scholar 

  76. Hou P, Ji M, Xing M. Association of PTEN gene methylation with genetic alterations in the phosphatidylinositol 3-kinase/AKT signaling pathway in thyroid tumors. Cancer. 2008;113(9):2440–7.

    Article  CAS  PubMed  Google Scholar 

  77. Bedolla R, Prihoda TJ, Kreisberg JI, Malik SN, Krishnegowda NK, Troyer DA, et al. Determining risk of biochemical recurrence in prostate cancer by immunohistochemical detection of PTEN expression and Akt activation. Clin Cancer Res. 2007;13(13):3860–7.

    Article  CAS  PubMed  Google Scholar 

  78. Lu HY, Qin J, Han N, Lei L, Xie F, Li C. EGFR, KRAS, BRAF, PTEN, and PIK3CA mutation in plasma of small cell lung cancer patients. Onco Targets Ther. 2018;11:2217–26. 

  79. Mikhail M, Velazquez E, Shapiro R, Berman R, Pavlick A, Sorhaindo L, et al. PTEN expression in melanoma: relationship with patient survival, Bcl-2 expression, and proliferation. Clin Cancer Res. 2005;11(14):5153–7.

    Article  CAS  PubMed  Google Scholar 

  80. Dal Col J, Zancai P, Terrin L, Guidoboni M, Ponzoni M, Pavan A, et al. Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood. 2008;111(10):5142–51.

    Article  CAS  PubMed  Google Scholar 

  81. Shao X, Tandon R, Samara G, Kanki H, Yano H, Close LG, et al. Mutational analysis of the PTEN gene in head and neck squamous cell carcinoma. Int J Cancer. 1998;77(5):684–8.

    Article  CAS  PubMed  Google Scholar 

  82. Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res. 2005;94:29–86.

  83. Hyman DM, Smyth LM, Donoghue MTA, Westin SN, Bedard PL, Dean EJ, et al. AKT inhibition in solid tumors with AKT1 mutations. J Clin Oncol. 2017;35(20):2251–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Bleeker FE, Felicioni L, Buttitta F, Lamba S, Cardone L, Rodolfo M, et al. AKT1(E17K) in human solid tumours. Oncogene. 2008;27(42):5648–50.

    Article  CAS  PubMed  Google Scholar 

  85. Pickering CR, Zhang J, Yoo SY, Bengtsson L, Moorthy S, Neskey DM, et al. Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Discov. 2013;3(7):770–81.

    Article  CAS  PubMed  Google Scholar 

  86. Eom HS, Kim MS, Hur SY, Yoo NJ, Lee SH. Absence of oncogenic AKT1 E17K mutation in prostate, esophageal, laryngeal and urothelial carcinomas, hepatoblastomas, gastrointestinal stromal tumors and malignant meningiomas. Acta Oncol. 2009;48(7):1084–5.

    Article  CAS  PubMed  Google Scholar 

  87. Kim MS, Jeong EG, Yoo NJ, Lee SH. Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias. Br J Cancer. 2008;98(9):1533–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. de Souza JA, Davis DW, Zhang Y, Khattri A, Seiwert TY, Aktolga S, et al. A phase II study of lapatinib in recurrent/metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res. 2012;18(8):2336–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Manley PW, Cowan-Jacob SW, Mestan J. Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia. Biochim Biophys Acta. 2005;1754(1–2):3–13.

    Article  CAS  PubMed  Google Scholar 

  90. Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, et al. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47(27):6658–61.

    Article  CAS  PubMed  Google Scholar 

  91. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol. 2010;28(6):1075–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wierstra I. The transcription factor FOXM1 (Forkhead box M1): proliferation-specific expression, transcription factor function, target genes, mouse models, and normal biological roles. Adv Cancer Res. 2013;118:97–398.

    Article  CAS  PubMed  Google Scholar 

  93. Halasi M, Gartel AL. FOX(M1) news--it is cancer. Mol Cancer Ther. 2013;12(3):245–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Gemenetzidis E, Bose A, Riaz AM, Chaplin T, Young BD, Ali M, et al. FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation. PLoS One. 2009;4(3):e4849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Teh MT, Gemenetzidis E, Patel D, Tariq R, Nadir A, Bahta AW, et al. FOXM1 induces a global methylation signature that mimics the cancer epigenome in head and neck squamous cell carcinoma. PLoS One. 2012;7(3):e34329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Gemenetzidis E, Elena-Costea D, Parkinson EK, Waseem A, Wan H, Teh MT. Induction of human epithelial stem/progenitor expansion by FOXM1. Cancer Res. 2010;70(22):9515–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lambert M, Jambon S, Depauw S, David-Cordonnier MH. Targeting Transcription Factors for Cancer Treatment. Molecules. 2018;23(6). https://doi.org/10.3390/molecules23061479.

  98. Yang N, Wang C, Wang Z, Zona S, Lin SX, Wang X, et al. FOXM1 recruits nuclear Aurora kinase a to participate in a positive feedback loop essential for the self-renewal of breast cancer stem cells. Oncogene. 2017;36(24):3428–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wang IC, Chen YJ, Hughes D, Petrovic V, Major ML, Park HJ, et al. Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Mol Cell Biol. 2005;25(24):10875–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hoellein A, Pickhard A, von Keitz F, Schoeffmann S, Piontek G, Rudelius M, et al. Aurora kinase inhibition overcomes cetuximab resistance in squamous cell cancer of the head and neck. Oncotarget. 2011;2(8):599–609.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Reiter R, Gais P, Jütting U, Steuer-Vogt MK, Pickhard A, Bink K, et al. Aurora kinase a messenger RNA overexpression is correlated with tumor progression and shortened survival in head and neck squamous cell carcinoma. Clin Cancer Res. 2006;12(17):5136–41.

    Article  CAS  PubMed  Google Scholar 

  102. Kelly KR, Ecsedy J, Mahalingam D, Nawrocki ST, Padmanabhan S, Giles FJ et al. Targeting aurora kinases in cancer treatment. Curr Drug Targets. 2011;12(14):2067–78.

  103. Hung LY, Tseng JT, Lee YC, Xia W, Wang YN, Wu ML, et al. Nuclear epidermal growth factor receptor (EGFR) interacts with signal transducer and activator of transcription 5 (STAT5) in activating Aurora-a gene expression. Nucleic Acids Res. 2008;36(13):4337–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Lai CH, Tseng JT, Lee YC, Chen YJ, Lee JC, Lin BW, et al. Translational up-regulation of Aurora-a in EGFR-overexpressed cancer. J Cell Mol Med. 2010;14(6b):1520–31.

    Article  CAS  PubMed  Google Scholar 

  105. Miracca EC, Kowalski LP, Nagai MA. High prevalence of p16 genetic alterations in head and neck tumours. Br J Cancer. 1999;81(4):677–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Cordon-Cardo C. Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol. 1995;147(3):545–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Rosenberg CL, Kim HG, Shows TB, Kronenberg HM, Arnold A. Rearrangement and overexpression of D11S287E, a candidate oncogene on chromosome 11q13 in benign parathyroid tumors. Oncogene. 1991;6(3):449–53.

    CAS  PubMed  Google Scholar 

  108. Akiyama N, Tsuruta H, Sasaki H, Sakamoto H, Hamaguchi M, Ohmura Y, et al. Messenger RNA levels of five genes located at chromosome 11q13 in B-cell tumors with chromosome translocation t(11;14)(q13;q32). Cancer Res. 1994;54(2):377–9.

    CAS  PubMed  Google Scholar 

  109. Lammie GA, Fantl V, Smith R, Schuuring E, Brookes S, Michalides R, et al. D11S287, a putative oncogene on chromosome 11q13, is amplified and expressed in squamous cell and mammary carcinomas and linked to BCL-1. Oncogene. 1991;6(3):439–44.

    CAS  PubMed  Google Scholar 

  110. Smeets SJ, Braakhuis BJM, Abbas S, Snijders PJF, Ylstra B, van de Wiel MA, et al. Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus. Oncogene. 2006;25(17):2558–64.

    Article  CAS  PubMed  Google Scholar 

  111. Jiang W, Kahn SM, Zhou P, Zhang YJ, Cacace AM, Infante AS, et al. Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control, cell cycle progression and gene expression. Oncogene. 1993;8(12):3447–57.

    CAS  PubMed  Google Scholar 

  112. Michalides R, van Veelen N, Hart A, Loftus B, Wientjens E, Balm A. Overexpression of cyclin D1 correlates with recurrence in a group of forty-seven operable squamous cell carcinomas of the head and neck. Cancer Res. 1995;55(5):975–8.

    CAS  PubMed  Google Scholar 

  113. Fracchiolla NS, Pruneri G, Pignataro L, Carboni N, Capaccio P, Boletini A, et al. Molecular and immunohistochemical analysis of the bcl-1/cyclin D1 gene in laryngeal squamous cell carcinomas: correlation of protein expression with lymph node metastases and advanced clinical stage. Cancer. 1997;79(6):1114–21.

    Article  CAS  PubMed  Google Scholar 

  114. Meredith SD, Levine PA, Burns JA, Gaffey MJ, Boyd JC, Weiss LM, et al. Chromosome 11q13 amplification in head and neck squamous cell carcinoma. Association with poor prognosis. Arch Otolaryngol Head Neck Surg. 1995;121(7):790–4.

    Article  CAS  PubMed  Google Scholar 

  115. Tatsuka M, Sato S, Kitajima S, Suto S, Kawai H, Miyauchi M, et al. Overexpression of Aurora-a potentiates HRAS-mediated oncogenic transformation and is implicated in oral carcinogenesis. Oncogene. 2005;24(6):1122–7.

    Article  CAS  PubMed  Google Scholar 

  116. Chen CH, Chang AYW, Li SH, Tsai HT, Shiu LY, Su LJ, et al. Suppression of Aurora-A-FLJ10540 signaling axis prohibits the malignant state of head and neck cancer. Mol Cancer. 2015;14:83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Pan C, Yan M, Yao J, Xu J, Long Z, Huang H, et al. Aurora kinase small molecule inhibitor destroys mitotic spindle, suppresses cell growth, and induces apoptosis in oral squamous cancer cells. Oral Oncol. 2008;44(7):639–45.

    Article  CAS  PubMed  Google Scholar 

  118. Pannone G, Hindi SAH, Santoro A, Sanguedolce F, Rubini C, Cincione RI, et al. Aurora B expression as a prognostic indicator and possible therapeutic target in oral squamous cell carcinoma. Int J Immunopathol Pharmacol. 2011;24(1):79–88.

    Article  CAS  PubMed  Google Scholar 

  119. Flynn J, Jones J, Johnson AJ, Andritsos L, Maddocks K, Jaglowski S, et al. Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia. Leukemia. 2015;29(7):1524–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Martin MP, Olesen SH, Georg GI, Schönbrunn E. Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains. ACS Chem Biol. 2013;8(11):2360–5.

    Article  CAS  PubMed  Google Scholar 

  121. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3(11):1427–38.

    CAS  PubMed  Google Scholar 

  122. Hanks SK, Hunter T. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 1995;9(8):576–96.

    Article  CAS  PubMed  Google Scholar 

  123. Mita MM, Joy AA, Mita A, Sankhala K, Jou YM, Zhang D, et al. Randomized phase II trial of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus capecitabine in patients with advanced breast cancer. Clin Breast Cancer. 2014;14(3):169–76.

    Article  CAS  PubMed  Google Scholar 

  124. Garcia Martinez J, Pérez-Escuredo J, García-Carracedo D, Alonso-Guervós M, Suárez-Nieto C, Llorente-Pendás JL, et al. Analysis of microsatellite instability in laryngeal squamous cell carcinoma. Acta Otorrinolaringol Esp. 2012;63(2):79–84.

  125. van der Riet P, Nawroz H, Hruban RH, Corio R, Tokino K, Koch W, et al. Frequent loss of chromosome 9p21-22 early in head and neck cancer progression. Cancer Res. 1994;54(5):1156–8.

    PubMed  Google Scholar 

  126. Kamb A, Gruis N, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian S, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994;264(5157):436–40.

    Article  CAS  PubMed  Google Scholar 

  127. Li J, Poi MJ, Tsai MD. Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer. Biochemistry. 2011;50(25):5566–82.

    Article  CAS  PubMed  Google Scholar 

  128. Lesnikova I, Lidang M, Hamilton-Dutoit S, Koch J. p16 as a diagnostic marker of cervical neoplasia: a tissue microarray study of 796 archival specimens. Diagn Pathol. 2009;4:22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Kobayashi K, Hisamatsu K, Suzui N, Hara A, Tomita H, Miyazaki T. A Review of HPV-Related Head and Neck Cancer. J Clin Med. 2018;7(9). https://doi.org/10.3390/jcm7090241.

  130. Mori T, Miura K, Aoki T, Nishihira T, Mori S, Nakamura Y. Frequent somatic mutation of the MTS1/CDK4I (multiple tumor suppressor/cyclin-dependent kinase 4 inhibitor) gene in esophageal squamous cell carcinoma. Cancer Res. 1994;54(13):3396–7.

    CAS  PubMed  Google Scholar 

  131. Yeudall WA, Crawford RY, Ensley J, Robbins K. MTS1/CDK4I is altered in cell lines derived from primary and metastatic oral squamous cell carcinoma. Carcinogenesis. 1994;15(12):2683–6.

    Article  CAS  PubMed  Google Scholar 

  132. Reed AL, Califano J, Cairns P, Westra WH, Jones RM, Koch W, et al. High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cell carcinoma. Cancer Res. 1996;56(16):3630–3.

    CAS  PubMed  Google Scholar 

  133. El-Naggar AK, Lai S, Clayman G, Lee JK, Luna MA, Goepfert H et al. Methylation, a major mechanism of p16/CDKN2 gene inactivation in head and neck squamous carcinoma. Am J Pathol. 1997;151(6):1767–74.

  134. Asokan GS, Jeelani S, Gnanasundaram N. Promoter hypermethylation profile of tumour suppressor genes in oral leukoplakia and oral squamous cell carcinoma. J Clin Diagn Res. 2014;8(10):Zc09–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Diez-Perez R, Campo-Trapero J, Cano-Sánchez J, López-Durán M, Gonzalez-Moles MA, Bascones-Ilundain J, et al. Methylation in oral cancer and pre-cancerous lesions (review). Oncol Rep. 2011;25(5):1203–9.

  136. Hannon GJ, Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 1994;371(6494):257–61.

    Article  CAS  PubMed  Google Scholar 

  137. Herman JG, Jen J, Merlo A, Baylin SB. Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res. 1996;56(4):722–7.

    CAS  PubMed  Google Scholar 

  138. Drexler HG. Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells. Leukemia. 1998;12(6):845–59.

    Article  CAS  PubMed  Google Scholar 

  139. Reiss M, Munoz-Antonia T, Cowan JM, Wilkins PC, Zhou ZL, Vellucci VF. Resistance of human squamous carcinoma cells to transforming growth factor beta 1 is a recessive trait. Proc Natl Acad Sci U S A. 1993;90(13):6280–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Prime SS, Matthews JB, Patel V, Game SM, Donnelly M, Stone A, et al. TGF-beta receptor regulation mediates the response to exogenous ligand but is independent of the degree of cellular differentiation in human oral keratinocytes. Int J Cancer. 1994;56(3):406–12.

    Article  CAS  PubMed  Google Scholar 

  141. Edmiston JS, Yeudall WA, Chung TD, Lebman DA. Inability of transforming growth factor-beta to cause SnoN degradation leads to resistance to transforming growth factor-beta-induced growth arrest in esophageal cancer cells. Cancer Res. 2005;65(11):4782–8.

    Article  CAS  PubMed  Google Scholar 

  142. Lane D, Levine A. p53 research: the past thirty years and the next thirty years. Cold Spring Harb Perspect Biol. 2010;2(12):a000893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Barsotti AM, Prives C. Pro-proliferative FoxM1 is a target of p53-mediated repression. Oncogene. 2009;28(48):4295–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Chen SS, Chang PC, Cheng YW, Tang FM, Lin YS. Suppression of the STK15 oncogenic activity requires a transactivation-independent p53 function. EMBO J. 2002;21(17):4491–9.

  145. Poeta ML, Manola J, Goldwasser MA, Forastiere A, Benoit N, Califano JA, et al. TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med. 2007;357(25):2552–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. van Houten VM, Tabor MP, van den Brekel MWM, Alain Kummer J, Denkers F, Dijkstra J, et al. Mutated p53 as a molecular marker for the diagnosis of head and neck cancer. J Pathol. 2002;198(4):476–86.

    Article  CAS  PubMed  Google Scholar 

  147. Balz V, Scheckenbach K, Götte K, Bockmühl U, Petersen I, Bier H. 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. 2003;63(6):1188–91.

    CAS  PubMed  Google Scholar 

  148. Zhou G, Liu Z, Myers JN. TP53 mutations in head and neck squamous cell carcinoma and their impact on disease progression and treatment response. J Cell Biochem. 2016;117(12):2682–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev. 2012;26(12):1268–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Rippin TM, Bykov VJN, Freund SMV, Selivanova G, Wiman KG, Fersht AR. Characterization of the p53-rescue drug CP-31398 in vitro and in living cells. Oncogene. 2002;21(14):2119–29.

    Article  CAS  PubMed  Google Scholar 

  151. Brockstein B, Haraf DJ, Rademaker AW, Kies MS, Stenson KM, Rosen F, et al. Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional experience. Ann Oncol. 2004;15(8):1179–86.

    Article  CAS  PubMed  Google Scholar 

  152. Cappuzzo F, Jänne PA, Skokan M, Finocchiaro G, Rossi E, Ligorio C, et al. MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients. Ann Oncol. 2009;20(2):298–304.

    Article  CAS  PubMed  Google Scholar 

  153. Machiels JP, et al. Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006-01. J Clin Oncol. 2010;28(1):21–8.

    Article  CAS  PubMed  Google Scholar 

  154. Choong NW, Kozloff M, Taber D, Hu HS, Wade J, Ivy P, et al. Phase II study of sunitinib malate in head and neck squamous cell carcinoma. Investig New Drugs. 2010;28(5):677–83.

    Article  CAS  Google Scholar 

  155. Bauman JE, Arias-Pulido H, Lee SJ, Fekrazad MH, Ozawa H, Fertig E, et al. A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma. Oral Oncol. 2013;49(5):461–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Lu M, Zhan X. The crucial role of multiomic approach in cancer research and clinically relevant outcomes. EPMA J. 2018;9(1):77–102.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Ishikawa S, Wong DTW, Sugimoto M, Gleber-Netto FO, Li F, Tu M, et al. Identification of salivary metabolites for oral squamous cell carcinoma and oral epithelial dysplasia screening from persistent suspicious oral mucosal lesions. Clin Oral Investig. 2018.

  158. Aro K, Wei F, Wong DT, Tu M. Saliva Liquid Biopsy for Point-of-Care Applications. Front Public Health. 2017;5(77). https://doi.org/10.3389/fpubh.2017.00077..

  159. Cheng J, Nonaka T, Wong DTW. Salivary exosomes as Nanocarriers for Cancer biomarker delivery. Materials. 2019;12(4):654.

    Article  PubMed Central  Google Scholar 

  160. Li F, Kaczor-Urbanowicz KE, Sun J, Majem B, Lo HC, Kim Y, et al. Characterization of human salivary extracellular RNA by next-generation sequencing. Clin Chem. 2018;64(7):1085–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Nonaka T, Wong DTW. Liquid biopsy in head and neck Cancer: promises and challenges. J Dent Res. 2018;97(6):701–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Wang Y, Springer S, Mulvey CL, Silliman N, Schaefer J, Sausen M, et al. Detection of somatic mutations and HPV in the saliva and plasma of patients with head and neck squamous cell carcinomas. Sci Transl Med. 2015;7(293):293ra104.

  163. Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 2011;333(6046):1154–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333(6046):1157–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Cohen EEW, Licitra LF, Burtness B, Fayette J, Gauler T, Clement PM, et al. Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer. Ann Oncol. 2017;28(10):2526–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Zhan X, Long Y, Lu M. Exploration of variations in proteome and metabolome for predictive diagnostics and personalized treatment algorithms: innovative approach and examples for potential clinical application. J Proteome. 2018;188:30–40.

    Article  CAS  Google Scholar 

Download references

Funding

R01-DE024381.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to W. Andrew Yeudall.

Ethics declarations

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethical approval

Not applicable.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shahoumi, L.A., Yeudall, W.A. Targeted therapies for non-HPV-related head and neck cancer: challenges and opportunities in the context of predictive, preventive, and personalized medicine. EPMA Journal 10, 291–305 (2019). https://doi.org/10.1007/s13167-019-00177-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13167-019-00177-y

Keywords

  • EGFR
  • Signal transduction
  • Cell cycle
  • p53
  • Molecular targets
  • Predictive preventive personalized medicine
  • PPPM