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Targeting the ErbB Family in Head and Neck Cancer

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Molecular Determinants of Head and Neck Cancer

Part of the book series: Current Cancer Research ((CUCR))

Abstract

Members of the ErbB receptor tyrosine kinase family (EGFR, HER2, HER3, and HER4), which regulate cell differentiation, proliferation, and survival, are commonly overexpressed and hyperactivated in squamous cell carcinoma of the head and neck (SCCHN). This abnormal expression and activity triggers multiple effector cascades that promote cancer growth, involving signaling through Ras-Raf-ERK1/2, PI3K/AKT/mTOR, JAK1/STAT3, PLC/PKC, and others. Targeting of EGFR remains one of the most common therapies for patients with SCCHN, with newer therapies also targeting additional ErbB family members and ErbB effectors, and exploring combinatorial approaches. In this chapter, we will describe the biology of ErbB family receptors in normal cells and in SCCHN, current and novel therapeutic approaches, and mechanisms underlying resistance to anti-EGFR therapy.

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References

  1. Cowley GP, Smith JA, Gusterson BA. Increased EGF receptors on human squamous carcinoma cell lines. Br J Cancer. 1986;53(2):223–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Stanton P, et al. Epidermal growth factor receptor expression by human squamous cell carcinomas of the head and neck, cell lines and xenografts. Br J Cancer. 1994;70(3):427–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Bassiri M, Privalsky ML. Mutagenesis of the avian erythroblastosis virus erbB coding region: an intact extracellular domain is not required for oncogenic transformation. J Virol. 1986;59(2):525–30.

    PubMed  PubMed Central  CAS  Google Scholar 

  4. Bouyain S, et al. The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand. Proc Natl Acad Sci. 2005;102(42):15024–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cho HS. Structure of the extracellular region of HER3 reveals an interdomain tether. Science. 2002;297(5585):1330–3.

    Article  CAS  PubMed  Google Scholar 

  6. Franklin MC, et al, Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. 2004, Protein Data Bank, Rutgers University.

    Google Scholar 

  7. Shi F, et al. ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation. Proc Natl Acad Sci. 2010;107(17):7692–7.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Jura N, et al. Catalytic control in the EGF receptor and its connection to general kinase regulatory mechanisms. Mol Cell. 2011;42(1):9–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Zhang X, et al. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell. 2006;125(6):1137–49.

    Article  CAS  PubMed  Google Scholar 

  10. Jura N, et al. Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3. Proc Natl Acad Sci U S A. 2009;106(51):21608–13.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Grandis JR, Tweardy DJ. TGF-α and EGFR in head and neck cancer. J Cell Biochem. 1993;53(S17F):188–91.

    Article  Google Scholar 

  12. 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.

    CAS  PubMed  Google Scholar 

  13. Hitt R, et al. Prognostic value of the epidermal growth factor receptor (EGRF) and p53 in advanced head and neck squamous cell carcinoma patients treated with induction chemotherapy. Eur J Cancer. 2005;41(3):453–60.

    Article  CAS  PubMed  Google Scholar 

  14. Liccardi G, Hartley JA, Hochhauser D. EGFR nuclear translocation modulates DNA repair following cisplatin and ionizing radiation treatment. Cancer Res. 2011;71(3):1103–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Ang KK, 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.

    CAS  PubMed  Google Scholar 

  16. Keren S, et al. Role of EGFR as a prognostic factor for survival in head and neck cancer: a meta-analysis. Tumour Biol. 2014;35(3):2285–95.

    Article  CAS  PubMed  Google Scholar 

  17. Kalyankrishna S, Grandis JR. Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol. 2006;24(17):2666–72.

    Article  CAS  PubMed  Google Scholar 

  18. Mehra R, et al. Protein-intrinsic and signaling network-based sources of resistance to EGFR- and ErbB family-targeted therapies in head and neck cancer. Drug Resist Updat. 2011;14(6):260–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Lui VW, et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov. 2013;3(7):761–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. O’Rorke MA, et al. Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis. Oral Oncol. 2012;48(12):1191–201.

    Article  PubMed  Google Scholar 

  21. Husain H, et al. Nuclear epidermal growth factor receptor and p16 expression in head and neck squamous cell carcinoma. Laryngoscope. 2012;122(12):2762–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Kim SH, et al. Human papillomavirus 16 E5 up-regulates the expression of vascular endothelial growth factor through the activation of epidermal growth factor receptor, MEK/ ERK1,2 and PI3K/Akt. Cell Mol Life Sci. 2006;63(7–8):930–8.

    Article  CAS  PubMed  Google Scholar 

  23. Straight SW, Herman B, McCance DJ. The E5 oncoprotein of human papillomavirus type 16 inhibits the acidification of endosomes in human keratinocytes. J Virol. 1995;69(5):3185–92.

    PubMed  PubMed Central  CAS  Google Scholar 

  24. Weiner LM, Surana R, Wang S. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol. 2010;10(5):317–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Rabinowits G, Haddad RI. Overcoming resistance to EGFR inhibitor in head and neck cancer: a review of the literature. Oral Oncol. 2012;48(11):1085–9.

    Article  CAS  PubMed  Google Scholar 

  26. Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009;9(1):28–39.

    Article  CAS  PubMed  Google Scholar 

  27. Mancini M, et al. Combining three antibodies nullifies feedback-mediated resistance to erlotinib in lung cancer. Sci Signal. 2015;8(379):ra53.

    Article  CAS  PubMed  Google Scholar 

  28. Wilson KJ, et al. Functional selectivity of EGF family peptide growth factors: implications for cancer. Pharmacol Ther. 2009;122(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  29. Burgess AW, et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell. 2003;12(3):541–52.

    Article  CAS  PubMed  Google Scholar 

  30. Ferguson KM, et al. EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Mol Cell. 2003;11(2):507–17.

    Article  CAS  PubMed  Google Scholar 

  31. Cho H-S, et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin fab. Nature. 2003;421(6924):756–60.

    Article  CAS  PubMed  Google Scholar 

  32. Garrett TPJ, et al. Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α. Cell. 2002;110(6):763–73.

    Article  CAS  PubMed  Google Scholar 

  33. Haskins JW, Nguyen DX, Stern DF. Neuregulin 1-activated ERBB4 interacts with YAP to induce hippo pathway target genes and promote cell migration. Sci Signal. 2014;7(355):ra116.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Schlessinger J. Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell. 2002;110(6):669–72.

    Article  CAS  PubMed  Google Scholar 

  35. Rogers SJ, et al. Biological significance of c-erbB family oncogenes in head and neck cancer. Cancer Metastasis Rev. 2005;24(1):47–69.

    Article  CAS  PubMed  Google Scholar 

  36. Bragin PE, et al. HER2 transmembrane domain dimerization coupled with self-association of membrane-embedded cytoplasmic juxtamembrane regions. J Mol Biol. 2016;428(1):52–61.

    Article  CAS  PubMed  Google Scholar 

  37. Shan Y, et al. Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization. Cell. 2012;149(4):860–70.

    Article  CAS  PubMed  Google Scholar 

  38. Red Brewer M, et al. Mechanism for activation of mutated epidermal growth factor receptors in lung cancer. Proc Natl Acad Sci U S A. 2013;110(38):E3595–604.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Endres NF, et al. Regulation of the catalytic activity of the EGF receptor. Curr Opin Struct Biol. 2011;21(6):777–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Alvarado D, Klein DE, Lemmon MA. Structural basis for negative cooperativity in growth factor binding to an EGF receptor. Cell. 2010;142(4):568–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Ghosh R, et al. Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers. Cancer Res. 2011;71(5):1871–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Landgraf R. HER2 therapy. HER2 (ERBB2): functional diversity from structurally conserved building blocks. Breast Cancer Res. 2007;9(1):202.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Wieduwilt MJ, Moasser MM. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell Mol Life Sci. 2008;65(10):1566–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Oksvold MP, et al. Serine mutations that abrogate ligand-induced ubiquitination and internalization of the EGF receptor do not affect c-Cbl association with the receptor. Oncogene. 2003;22(52):8509–18.

    Article  CAS  PubMed  Google Scholar 

  45. Oksvold MP, et al. UV-radiation-induced internalization of the epidermal growth factor receptor requires distinct serine and tyrosine residues in the cytoplasmic carboxy-terminal domain. Radiat Res. 2004;161(6):685–91.

    Article  CAS  PubMed  Google Scholar 

  46. Tong J, et al. Epidermal growth factor receptor phosphorylation sites Ser991 and Tyr998 are implicated in the regulation of receptor endocytosis and phosphorylations at Ser1039 and Thr1041. Mol Cell Proteomics. 2009;8(9):2131–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Sousa LP, et al. Suppression of EGFR endocytosis by dynamin depletion reveals that EGFR signaling occurs primarily at the plasma membrane. Proc Natl Acad Sci U S A. 2012;109(12):4419–24.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Orth JD, et al. A novel endocytic mechanism of epidermal growth factor receptor sequestration and internalization. Cancer Res. 2006;66(7):3603–10.

    Article  CAS  PubMed  Google Scholar 

  49. Sigismund S, et al. Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable for degradation. Dev Cell. 2008;15(2):209–19.

    Article  CAS  PubMed  Google Scholar 

  50. Schoeberl B, et al. An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Res. 2010;70(6):2485–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Tan X, et al. Stress-induced EGFR trafficking: mechanisms, functions, and therapeutic implications. Trends Cell Biol. 2016;26(5):352–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Dutta S, et al. Neuropilin-2 regulates endosome maturation and EGFR trafficking to support Cancer cell pathobiology. Cancer Res. 2016;76(2):418–28.

    Article  CAS  PubMed  Google Scholar 

  53. Lee H, et al. Anks1a regulates COPII-mediated anterograde transport of receptor tyrosine kinases critical for tumorigenesis. Nat Commun. 2016;7:12799.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Jeong J, et al. PMCA2 regulates HER2 protein kinase localization and signaling and promotes HER2-mediated breast cancer. Proc Natl Acad Sci U S A. 2016;113(3):E282–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Lang SA, et al. Inhibition of heat shock protein 90 impairs epidermal growth factor-mediated signaling in gastric cancer cells and reduces tumor growth and vascularization in vivo. Mol Cancer Ther. 2007;6(3):1123–32.

    Article  CAS  PubMed  Google Scholar 

  56. Chung CH, 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.

    Article  CAS  PubMed  Google Scholar 

  57. Grandis JR, et al. Levels of TGF- and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst. 1998;90(11):824–32.

    Article  Google Scholar 

  58. Maurizi M, et al. Prognostic significance of epidermal growth factor receptor in laryngeal squamous cell carcinoma. Br J Cancer. 1996;74(8):1253–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Temam S, 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.

    Article  CAS  PubMed  Google Scholar 

  60. Ongkeko WM, et al. Expression of protein tyrosine kinases in head and neck squamous cell carcinomas. Am J Clin Pathol. 2005;124(1):71–6.

    Article  CAS  PubMed  Google Scholar 

  61. Bei R, et al. Frequent overexpression of multiple ErbB receptors by head and neck squamous cell carcinoma contrasts with rare antibody immunity in patients. J Pathol. 2004;204(3):317–25.

    Article  CAS  PubMed  Google Scholar 

  62. Bernardes VF, et al. EGFR status in oral squamous cell carcinoma: comparing immunohistochemistry, FISH and CISH detection in a case series study. BMJ Open. 2013;3(1):e002077.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Pectasides E, et al. Comparative prognostic value of epidermal growth factor quantitative protein expression compared with FISH for head and neck squamous cell carcinoma. Clin Cancer Res. 2011;17(9):2947–54.

    Article  CAS  PubMed  Google Scholar 

  64. Beck TN, Golemis EA. Genomic insights into head and neck cancer. Cancers of the Head & Neck. 2016;1(1):1.

    Article  Google Scholar 

  65. Gao J, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Cerami E, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4.

    Article  PubMed  Google Scholar 

  67. Feldman R, et al. Molecular profiling of head and neck squamous cell carcinoma. Head Neck. 2015;38(S1):E1625–38.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Rubin Grandis J, et al. Quantitative immunohistochemical analysis of transforming growth factor-alpha and epidermal growth factor receptor in patients with squamous cell carcinoma of the head and neck. Cancer. 1996;78(6):1284–92.

    Article  CAS  PubMed  Google Scholar 

  69. Shin DM, et al. Dysregulation of epidermal growth factor receptor expression in premalignant lesions during head and neck tumorigenesis. Cancer Res. 1994;54(12):3153–9.

    CAS  PubMed  Google Scholar 

  70. Chang AR, et al. Expression of epidermal growth factor receptor and cyclin D1 in pretreatment biopsies as a predictive factor of radiotherapy efficacy in early glottic cancer. Head Neck. 2008;30(7):852–7.

    Article  PubMed  Google Scholar 

  71. Alterio D, et al. Role of EGFR as prognostic factor in head and neck cancer patients treated with surgery and postoperative radiotherapy: proposal of a new approach behind the EGFR overexpression. Med Oncol. 2017;34(6):107.

    Article  CAS  PubMed  Google Scholar 

  72. Morgan S, Grandis JR. ErbB receptors in the biology and pathology of the aerodigestive tract. Exp Cell Res. 2009;315(4):572–82.

    Article  CAS  PubMed  Google Scholar 

  73. Bei R, et al. Co-localization of multiple ErbB receptors in stratified epithelium of oral squamous cell carcinoma. J Pathol. 2001;195(3):343–8.

    Article  CAS  PubMed  Google Scholar 

  74. Ekberg T, et al. Expression of EGFR, HER2, HER3, and HER4 in metastatic squamous cell carcinomas of the oral cavity and base of tongue. Int J Oncol. 2005;26(5):1177–85.

    CAS  PubMed  Google Scholar 

  75. Roepstorff K, et al. Endocytic downregulation of ErbB receptors: mechanisms and relevance in cancer. Histochem Cell Biol. 2008;129(5):563–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Huang C-C, et al. Cathepsin S attenuates endosomal EGFR signalling: a mechanical rationale for the combination of cathepsin S and EGFR tyrosine kinase inhibitors. Sci Rep. 2016;6:29256.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Rolle CE, et al. Expression and mutational analysis of c-CBL and its relationship to the MET receptor in head and neck squamous cell carcinoma. Oncotarget. 2017 Mar 21;8(12):18726–18734.

    Google Scholar 

  78. Ray D, et al. Regulation of EGFR protein stability by the HECT-type ubiquitin ligase SMURF2. Neoplasia. 2011;13(7):570–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Rajput A, et al. A novel mechanism of resistance to epidermal growth factor receptor antagonism in vivo. Cancer Res. 2007;67(2):665–73.

    Article  CAS  PubMed  Google Scholar 

  80. Jhappan C, et al. TGFα overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell. 1990;61(6):1137–46.

    Article  CAS  PubMed  Google Scholar 

  81. Matsui Y, et al. Development of mammary hyperplasia and neoplasia in MMTV-TGFα transgenic mice. Cell. 1990;61(6):1147–55.

    Article  CAS  PubMed  Google Scholar 

  82. Sandgren EP, et al. Overexpression of TGFα in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell. 1990;61(6):1121–35.

    Article  CAS  PubMed  Google Scholar 

  83. Tinhofer I, et al. Expression of Amphiregulin and EGFRvIII affect outcome of patients with squamous cell carcinoma of the head and neck receiving Cetuximab-docetaxel treatment. Clin Cancer Res. 2011;17(15):5197–204.

    Article  CAS  PubMed  Google Scholar 

  84. Yonesaka K, et al. Autocrine production of Amphiregulin predicts sensitivity to both Gefitinib and Cetuximab in EGFR wild-type cancers. Clin Cancer Res. 2008;14(21):6963–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Hatakeyama H, et al. Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired Cetuximab-resistance in head and neck squamous cell carcinoma. PLoS One. 2010;5(9):e12702.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Murakami H, et al. Transgenic mouse model for synergistic effects of nuclear oncogenes and growth factors in tumorigenesis: interaction of c-myc and transforming growth factor alpha in hepatic oncogenesis. Cancer Res. 1993;53(8):1719–23.

    CAS  PubMed  Google Scholar 

  87. Sandgren EP, et al. Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. Mol Cell Biol. 1993;13(1):320–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Sandgren EP, et al. Inhibition of mammary gland involution is associated with transforming growth factor alpha but not c-myc-induced tumorigenesis in transgenic mice. Cancer Res. 1995;55(17):3915–27.

    CAS  PubMed  Google Scholar 

  89. Oshima G, et al. Autocrine epidermal growth factor receptor ligand production and cetuximab response in head and neck squamous cell carcinoma cell lines. J Cancer Res Clin Oncol. 2012;138(3):491–9.

    Article  CAS  PubMed  Google Scholar 

  90. O-Charoenrat P, Rhys-Evans P, Eccles S. Expression and regulation of c-erbB ligands in human head and neck squamous carcinoma cells. Int J Cancer. 2000;88(5):759–65.

    Article  PubMed  CAS  Google Scholar 

  91. Gao J, Ulekleiv CH, Halstensen TS. Epidermal growth factor (EGF) receptor-ligand based molecular staging predicts prognosis in head and neck squamous cell carcinoma partly due to deregulated EGF-induced amphiregulin expression. J Exp Clin Cancer Res. 2016;35(1):151.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Wakasaki T, et al. A critical role of c-Cbl-interacting protein of 85 kDa in the development and progression of head and neck squamous cell carcinomas through the ras-ERK pathway. Neoplasia. 2010;12(10):789–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Brand TM, et al. The nuclear epidermal growth factor receptor signaling network and its role in cancer. Discov Med. 2011;12(66):419–32.

    PubMed  PubMed Central  Google Scholar 

  94. Matta A, Ralhan R. Overview of current and future biologically based targeted therapies in head and neck squamous cell carcinoma. Head Neck Oncol. 2009;1(1):6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Roskoski R. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res. 2012;66(2):105–43.

    Article  CAS  PubMed  Google Scholar 

  96. Wortzel I, Seger R. The ERK Cascade: distinct functions within various subcellular organelles. Genes Cancer. 2011;2(3):195–209.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Lurje G, Lenz H-J. EGFR signaling and drug discovery. Oncology. 2009;77(6):400–10.

    Article  CAS  PubMed  Google Scholar 

  98. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006;5(8):671–88.

    Article  CAS  PubMed  Google Scholar 

  99. Zheng LS, et al. SPINK6 promotes metastasis of nasopharyngeal carcinoma via binding and activation of epithelial growth factor receptor. Cancer Res. 2017;77(2):579–89.

    Article  CAS  PubMed  Google Scholar 

  100. Saloura V, et al. WHSC1L1-mediated EGFR mono-methylation enhances the cytoplasmic and nuclear oncogenic activity of EGFR in head and neck cancer. Sci Rep. 2017;7:40664.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Keller J, et al. Combination of phosphorylated and truncated EGFR correlates with higher tumor and nodal stage in head and neck cancer. Cancer Investig. 2010;28(10):1054–62.

    Article  CAS  Google Scholar 

  102. Hama T, et al. Prognostic significance of epidermal growth factor receptor phosphorylation and mutation in head and neck squamous cell carcinoma. Oncologist. 2009;14(9):900–8.

    Article  CAS  PubMed  Google Scholar 

  103. Schwentner I, et al. Identification of the rare EGFR mutation p.G796S as somatic and germline mutation in white patients with squamous cell carcinoma of the head and neck. Head Neck. 2008;30(8):1040–4.

    Article  PubMed  Google Scholar 

  104. Na II, et al. EGFR mutations and human papillomavirus in squamous cell carcinoma of tongue and tonsil. Eur J Cancer. 2007;43(3):520–6.

    Article  CAS  PubMed  Google Scholar 

  105. Lee JW. 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 

  106. Diedrich U, et al. Distribution of epidermal growth factor receptor gene amplification in brain tumours and correlation to prognosis. J Neurol. 1995;242(10):683–8.

    Article  CAS  PubMed  Google Scholar 

  107. Garcia de Palazzo IE, et al. Expression of mutated epidermal growth factor receptor by non-small cell lung carcinomas. Cancer Res. 1993;53(14):3217–20.

    CAS  PubMed  Google Scholar 

  108. Ge H, Gong X, Tang CK. Evidence of high incidence of EGFRvIII expression and coexpression with EGFR in human invasive breast cancer by laser capture microdissection and immunohistochemical analysis. Int J Cancer. 2002;98(3):357–61.

    Article  CAS  PubMed  Google Scholar 

  109. Moscatello DK, et al. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res. 1995;55(23):5536–9.

    CAS  PubMed  Google Scholar 

  110. Nishikawa R, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci. 1994;91(16):7727–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Okamoto I, et al. Expression of constitutively activated EGFRvlll in non-small cell lung cancer. Cancer Sci. 2003;94(1):50–6.

    Article  CAS  PubMed  Google Scholar 

  112. Chau NG, et al. The association between EGFR variant III, HPV, p16, c-MET, EGFR gene copy number and response to EGFR inhibitors in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Head Neck Oncol. 2011;3(1):11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Sok JC. 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.

    Article  CAS  PubMed  Google Scholar 

  114. Yang B, et al. Expression of epidermal growth factor receptor variant III in laryngeal carcinoma tissues. Auris Nasus Larynx. 2009;36(6):682–7.

    Article  PubMed  Google Scholar 

  115. McIntyre JB, et al. Specific and sensitive hydrolysis probe-based real-time PCR detection of epidermal growth factor receptor variant III in oral squamous cell carcinoma. PLoS One. 2012;7(2):e31723.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Melchers LJ, et al. Head and neck squamous cell carcinomas do not express EGFRvIII. Int J Radiat Oncol Biol Phys. 2014;90(2):454–62.

    Article  CAS  PubMed  Google Scholar 

  117. Stransky N, et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333(6046):1157–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Agrawal N, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 2011;333(6046):1154–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Chau NG, et al. Incorporation of next-generation sequencing into routine clinical care to direct treatment of head and neck squamous cell carcinoma. Clin Cancer Res. 2016;22(12):2939–49.

    Article  CAS  PubMed  Google Scholar 

  120. The Cancer Genome Atlas, N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82.

    Article  CAS  Google Scholar 

  121. Li H, et al. Genomic analysis of head and neck squamous cell carcinoma cell lines and human tumors: a rational approach to preclinical model selection. Mol Cancer Res. 2014;12(4):571–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Du L, et al. Overexpression of PIK3CA in murine head and neck epithelium drives tumor invasion and metastasis through PDK1 and enhanced TGFbeta signaling. Oncogene. 2016;35(35):4641–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Bozec A, et al. Combination of mTOR and EGFR targeting in an orthotopic xenograft model of head and neck cancer. Laryngoscope. 2016;126(4):E156–63.

    Article  CAS  PubMed  Google Scholar 

  124. Lai SY, Johnson FM. Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: implications for future therapeutic approaches. Drug Resist Updat. 2010;13(3):67–78.

    Article  CAS  PubMed  Google Scholar 

  125. Quesnelle KM, Boehm AL, Grandis JR. STAT-mediated EGFR signaling in cancer. J Cell Biochem. 2007;102(2):311–9.

    Article  CAS  PubMed  Google Scholar 

  126. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9(11):798–809.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Mali SB. Review of STAT3 (signal transducers and activators of transcription) in head and neck cancer. Oral Oncol. 2015;51(6):565–9.

    Article  CAS  PubMed  Google Scholar 

  128. Pectasides E, et al. Nuclear localization of signal transducer and activator of transcription 3 in head and neck squamous cell carcinoma is associated with a better prognosis. Clin Cancer Res. 2010;16(8):2427–34.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Wheeler SE, et al. Epidermal growth factor receptor variant III mediates head and neck cancer cell invasion via STAT3 activation. Oncogene. 2010;29(37):5135–45.

    Article  CAS  PubMed  Google Scholar 

  130. Bonner JA, et al. Enhancement of cetuximab-induced radiosensitization by JAK-1 inhibition. BMC Cancer. 2015;15:673.

    Google Scholar 

  131. Stegeman H, et al. Combining radiotherapy with MEK1/2, STAT5 or STAT6 inhibition reduces survival of head and neck cancer lines. Mol Cancer. 2013;12(1):133.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Hwang J-I, et al. Molecular cloning and characterization of a novel phospholipase C, PLC-η. Biochem J. 2005;389(1):181–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Thomas SM, et al. Epidermal growth factor receptor-stimulated activation of phospholipase Cgamma-1 promotes invasion of head and neck squamous cell carcinoma. Cancer Res. 2003;63(17):5629–35.

    CAS  PubMed  Google Scholar 

  134. Kassis J, et al. A role for phospholipase C-gamma-mediated signaling in tumor cell invasion. Clin Cancer Res. 1999;5(8):2251–60.

    CAS  PubMed  Google Scholar 

  135. Nozawa H, et al. Combined inhibition of PLC-1 and c-Src abrogates epidermal growth factor receptor-mediated head and neck squamous cell carcinoma invasion. Clin Cancer Res. 2008;14(13):4336–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Rosse C, et al. PKC and the control of localized signal dynamics. Nat Rev Mol Cell Biol. 2010;11(2):103–12.

    Article  CAS  PubMed  Google Scholar 

  137. Martínez-Gimeno C, et al. Alterations in levels of different protein kinase C isotypes and their influence on behavior of squamous cell carcinoma of the oral cavity: ɛPKC, a novel prognostic factor for relapse and survival. Head Neck. 1995;17(6):516–25.

    Article  PubMed  Google Scholar 

  138. Cohen EEW. Protein kinase C mediates epidermal growth factor-induced growth of head and neck tumor cells by regulating mitogen-activated protein kinase. Cancer Res. 2006;66(12):6296–303.

    Article  CAS  PubMed  Google Scholar 

  139. Elkabets M, et al. AXL mediates resistance to PI3Kalpha inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas. Cancer Cell. 2015;27(4):533–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Parsons SJ, Parsons JT. Src family kinases, key regulators of signal transduction. Oncogene. 2004;23(48):7906–9.

    Article  CAS  PubMed  Google Scholar 

  141. Koppikar P, et al. Combined inhibition of c-Src and epidermal growth factor receptor abrogates growth and invasion of head and neck squamous cell carcinoma. Clin Cancer Res. 2008;14(13):4284–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Egloff AM, Grandis JR. Improving response rates to EGFR-targeted therapies for head and neck squamous cell carcinoma: candidate predictive biomarkers and combination treatment with Src inhibitors. J Oncol. 2009;2009:1–12.

    Article  CAS  Google Scholar 

  143. Wheeler DL, Iida M, Dunn EF. The role of Src in solid tumors. Oncologist. 2009;14(7):667–78.

    Article  PubMed  CAS  Google Scholar 

  144. Xi S, et al. Src kinases mediate STAT growth pathways in squamous cell carcinoma of the head and neck. J Biol Chem. 2003;278(34):31574–83.

    Article  CAS  PubMed  Google Scholar 

  145. Zhang Q. Src family kinases mediate epidermal growth factor receptor ligand cleavage, proliferation, and invasion of head and neck Cancer cells. Cancer Res. 2004;64(17):6166–73.

    Article  CAS  PubMed  Google Scholar 

  146. Li C, et al. Nuclear EGFR contributes to acquired resistance to cetuximab. Oncogene. 2009;28(43):3801–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Yeatman TJ. A renaissance for SRC. Nat Rev Cancer. 2004;4(6):470–80.

    Article  CAS  PubMed  Google Scholar 

  148. Zhang X, et al. RANKL/RANK pathway abrogates cetuximab sensitivity in gastric cancer cells via activation of EGFR and c-Src. OncoTargets and Therapy. 2017;10:73–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Yamada T, et al. Receptor activator of NF-kappaB ligand induces cell adhesion and integrin alpha2 expression via NF-kappaB in head and neck cancers. Sci Rep. 2016;6:23545.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Yan M, et al. Correlation of NF-kappaB signal pathway with tumor metastasis of human head and neck squamous cell carcinoma. BMC Cancer. 2010;10:437.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Ferris RL, Grandis JR. NF-B gene signatures and p53 mutations in head and neck squamous cell carcinoma. Clin Cancer Res. 2007;13(19):5663–4.

    Article  CAS  PubMed  Google Scholar 

  152. Nakayama H, et al. High expression levels of nuclear factor κB, IκB kinase α and Akt kinase in squamous cell carcinoma of the oral cavity. Cancer. 2001;92(12):3037–44.

    Google Scholar 

  153. Yan B, et al. Genome-wide identification of novel expression signatures reveal distinct patterns and prevalence of binding motifs for p53, nuclear factor-κB and other signal transcription factors in head and neck squamous cell carcinoma. Genome Biol. 2007;8(5):R78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Arun P, et al. Nuclear NF-κB p65 phosphorylation at serine 276 by protein kinase A contributes to the malignant phenotype of head and neck cancer. Clin Cancer Res. 2009;15(19):5974–84.

    Google Scholar 

  155. Tanaka T, et al. Selective inhibition of nuclear factor-κB by nuclear factor-κB essential modulator-binding domain peptide suppresses the metastasis of highly metastatic oral squamous cell carcinoma. Cancer Sci. 2012;103(3):455–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Aravindan N, et al. Irreversible EGFR inhibitor EKB-569 targets low-LET γ-radiation-triggered Rel orchestration and potentiates cell death in squamous cell carcinoma. PLoS One. 2011;6(12):e29705.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Wilken R, et al. Curcumin: a review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol Cancer. 2011;10(1):12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Lee TL, et al. A signal network involving coactivated NF-κB and STAT3 and altered p53 modulates BAX/BCL-XL expression and promotes cell survival of head and neck squamous cell carcinomas. Int J Cancer. 2008;122(9):1987–98.

    Article  PubMed  CAS  Google Scholar 

  159. Bivona TG, et al. FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR. Nature. 2011;471(7339):523–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Li Z, et al. A positive feedback loop involving EGFR/Akt/mTORC1 and IKK/NF-kB regulates head and neck squamous cell carcinoma proliferation. Oncotarget. 2016;7(22):31892–906.

    PubMed  PubMed Central  Google Scholar 

  161. Kang H, Kiess A, Chung CH. Emerging biomarkers in head and neck cancer in the era of genomics. Nat Rev Clin Oncol. 2015;12(1):11–26.

    Article  PubMed  Google Scholar 

  162. Kalish LH, et al. Deregulated cyclin D1 expression is associated with decreased efficacy of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in head and neck squamous cell carcinoma cell lines. Clin Cancer Res. 2004;10(22):7764–74.

    Article  CAS  PubMed  Google Scholar 

  163. Namazie A, et al. Cyclin D1 amplification and p16(MTS1/CDK4I) deletion correlate with poor prognosis in head and neck tumors. Laryngoscope. 2002;112(3):472–81.

    Article  CAS  PubMed  Google Scholar 

  164. Beck TN, et al. EGFR and RB1 as dual biomarkers in HPV-negative head and neck Cancer. Mol Cancer Ther. 2016;15(10):2486.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Calais G, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst. 1999;91(24):2081–6.

    Article  CAS  PubMed  Google Scholar 

  166. Adelstein DJ, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent Chemoradiotherapy in patients with Unresectable squamous cell head and neck Cancer. J Clin Oncol. 2003;21(1):92–8.

    Article  PubMed  Google Scholar 

  167. Trotti A, et al. TAME: development of a new method for summarising adverse events of cancer treatment by the radiation therapy oncology group. Lancet Oncol. 2007;8(7):613–24.

    Article  PubMed  Google Scholar 

  168. Agulnik M. New approaches to EGFR inhibition for locally advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN). Med Oncol. 2012;29(4):2481–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Dittmann K, 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.

    Article  CAS  PubMed  Google Scholar 

  170. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of Cancer. J Clin Oncol. 2003;21(14):2787–99.

    Article  CAS  PubMed  Google Scholar 

  171. Vermorken JB, 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 

  172. Ferris RL, et al. Correlation of fc gamma receptor (fcγR) IIa and IIIa polymorphisms with clinical outcome in patients treated with Cetuximab-based Chemoradiation in the RTOG 0522 trial. Int J Radiat Oncol Biol Phys. 2014;88(2):467.

    Google Scholar 

  173. Dent P, 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Schmidt-Ullrich RK, et al. Altered expression of epidermal growth factor receptor and estrogen receptor in MCF-7 cells after single and repeated radiation exposures. Int J Radiat Oncol Biol Phys. 1994;29(4):813–9.

    Article  CAS  PubMed  Google Scholar 

  175. Bonner JA, 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 

  176. Ang KK, 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  PubMed  PubMed Central  CAS  Google Scholar 

  177. Fakih M, Vincent M. Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer. Curr Oncol. 2010;17(Suppl 1):S18–30.

    PubMed  PubMed Central  Google Scholar 

  178. Moon C, Chae YK, Lee J. Targeting epidermal growth factor receptor in head and neck cancer: lessons learned from cetuximab. Exp Biol Med. 2010;235(8):907–20.

    Article  CAS  Google Scholar 

  179. Sipples R. Common side effects of anti-EGFR therapy: Acneform rash. Semin Oncol Nurs. 2006;22:28–34.

    Article  PubMed  Google Scholar 

  180. Vermorken JB, et al. Platinum-based chemotherapy plus Cetuximab in head and neck Cancer. N Engl J Med. 2008;359(11):1116–27.

    Article  PubMed  CAS  Google Scholar 

  181. Masui H, et al. Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res. 1984;44(3):1002–7.

    CAS  PubMed  Google Scholar 

  182. Wheeler DL, Dunn EF, Harari PM. Understanding resistance to EGFR inhibitors—impact on future treatment strategies. Nat Rev Clin Oncol. 2010;7(9):493–507.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Mendelsohn J. Blockade of receptors for growth factors: an anticancer therapy—the fourth annual Joseph H Burchenal American Association of Cancer Research Clinical Research Award Lecture. Clin Cancer Res. 2000;6(3):747–53.

    CAS  PubMed  Google Scholar 

  184. Specenier P, Vermorken JB. Biologic therapy in head and neck Cancer: a road with hurdles. ISRN Oncology. 2012;2012:1–15.

    Article  CAS  Google Scholar 

  185. Schmitz KR, Ferguson KM. Interaction of antibodies with ErbB receptor extracellular regions. Exp Cell Res. 2009;315(4):659–70.

    Article  CAS  PubMed  Google Scholar 

  186. Marshall J. Clinical implications of the mechanism of epidermal growth factor receptor inhibitors. Cancer. 2006;107(6):1207–18.

    Article  PubMed  CAS  Google Scholar 

  187. Kurai J, et al. Antibody-dependent cellular cytotoxicity mediated by Cetuximab against lung Cancer cell lines. Clin Cancer Res. 2007;13(5):1552–61.

    Article  PubMed  CAS  Google Scholar 

  188. Mehra R, Cohen RB, Burtness BA. The role of cetuximab for the treatment of squamous cell carcinoma of the head and neck. Clin Adv Hematol Oncol. 2008;6(10):742–50.

    PubMed  PubMed Central  Google Scholar 

  189. Trigo J, et al. Cetuximab monotherapy is active in patients (pts) with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN): results of a phase II study. J Clin Oncol. 2004;22(14_suppl): 5502–5502.

    Google Scholar 

  190. Baselga J, et al. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol. 2000;18(4):904–14.

    Google Scholar 

  191. Robert F, et al. Phase I study of anti-epidermal growth factor receptor antibody Cetuximab in combination with radiation therapy in patients with advanced head and neck Cancer. J Clin Oncol. 2001;19(13):3234–43.

    Article  CAS  PubMed  Google Scholar 

  192. Bonner JA, et al. 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. 2010;11(1):21–8.

    Article  CAS  PubMed  Google Scholar 

  193. Baselga J, et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2005;23(24):5568–77.

    Article  PubMed  CAS  Google Scholar 

  194. Merlano M, Occelli M. Review of cetuximab in the treatment of squamous cell carcinoma of the head and neck. Ther Clin Risk Manag. 2007;3(5):871–6.

    PubMed  PubMed Central  CAS  Google Scholar 

  195. Burtness B, et al. 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 

  196. Licitra L, et al. Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: analysis of data from the EXTREME and CRYSTAL studies. Eur J Cancer. 2013;49(6):1161–8.

    Article  PubMed  CAS  Google Scholar 

  197. Lei Y, et al. EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1-TUFM protein complex. Oncogene. 2016;35(36):4698–707.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Srivastava RM, et al. Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients. Clin Cancer Res. 2013;19(7):1858–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  199. Nielsen DL, Pfeiffer P Jensen BV, Six cases of treatment with panitumumab in patients with severe hypersensitivity reactions to cetuximab. Ann Oncol. 2009;20(4):798–798.

    Google Scholar 

  200. Trivedi S, et al. Anti-EGFR targeted monoclonal antibody isotype influences antitumor cellular immunity in head and neck Cancer patients. Clin Cancer Res. 2016;22(21):5229–37.

    Article  PubMed  PubMed Central  Google Scholar 

  201. Wirth LJ, et al. Phase I dose-finding study of paclitaxel with panitumumab, carboplatin and intensity-modulated radiotherapy in patients with locally advanced squamous cell cancer of the head and neck. Ann Oncol. 2009;21(2):342–7.

    Article  PubMed  Google Scholar 

  202. Vermorken JB, et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol. 2013;14(8):697–710.

    Article  CAS  PubMed  Google Scholar 

  203. Siu LL, et al. Effect of standard radiotherapy with cisplatin vs accelerated radiotherapy with panitumumab in locoregionally advanced squamous cell head and neck carcinoma: a randomized clinical trial. JAMA Oncol. 2017;3(2):220–6.

    Article  PubMed  Google Scholar 

  204. Eriksen JG, et al. OC-009: update of the randomised phase III trial DAHANCA 19: primary C-RT or RT and zalutumumab for squamous cell carcinomas of head and neck. Radiother Oncol. 2015;114:10.

    Article  Google Scholar 

  205. Mateo C, et al. Humanization of a mouse monoclonal antibody that blocks the epidermal growth factor receptor: recovery of antagonistic activity. Immunotechnology. 1997;3(1):71–81.

    Article  CAS  PubMed  Google Scholar 

  206. Rivera F, et al. Current situation of Panitumumab, Matuzumab, Nimotuzumab and Zalutumumab. Acta Oncol. 2008;47(1):9–19.

    Article  CAS  PubMed  Google Scholar 

  207. Rojo F, et al. Pharmacodynamic trial of Nimotuzumab in Unresectable squamous cell carcinoma of the head and neck: a SENDO foundation study. Clin Cancer Res. 2010;16(8):2474–82.

    Article  CAS  PubMed  Google Scholar 

  208. Schmiedel J, et al. Matuzumab binding to EGFR prevents the conformational rearrangement required for dimerization. Cancer Cell. 2008;13(4):365–73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. Schanzer JM, et al. A novel glycoengineered bispecific antibody format for targeted inhibition of epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor type I (IGF-1R) demonstrating unique molecular properties. J Biol Chem. 2014;289(27):18693–706.

    Article  PubMed  PubMed Central  Google Scholar 

  210. Jones HE, et al. Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer. 2004;11(4):793–814.

    Article  CAS  PubMed  Google Scholar 

  211. Schanzer JM, et al. XGFR*, a novel affinity-matured bispecific antibody targeting IGF-1R and EGFR with combined signaling inhibition and enhanced immune activation for the treatment of pancreatic cancer. MAbs. 2016;8(4):811–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  212. Yonesaka K, et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody Cetuximab. Sci Transl Med. 2011;3(99):99ra86–99ra86.

    Google Scholar 

  213. Gutiérrez VF, et al. Genetic profile of second primary tumors and recurrences in head and neck squamous cell carcinomas. Head Neck. 2011;34(6):830–9.

    Article  PubMed  Google Scholar 

  214. Iida M, et al. Targeting the HER family with pan-HER effectively overcomes resistance to Cetuximab. Mol Cancer Ther. 2016;15(9):2175–86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Adams CW, et al. Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother. 2005;55(6):717–27.

    Article  CAS  PubMed  Google Scholar 

  216. Erjala K. Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor Gefitinib in head and neck squamous cell carcinoma cells. Clin Cancer Res. 2006;12(13):4103–11.

    Article  CAS  PubMed  Google Scholar 

  217. Schoeberl B, et al. Therapeutically targeting ErbB3: a key node in ligand-induced activation of the ErbB receptor-PI3K Axis. Sci Signal. 2009;2(77):ra31–ra31.

    Google Scholar 

  218. Huang J, et al. The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells. Mol Cancer. 2013;12(1):134.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  219. Liu JF, et al. Randomized phase II trial of Seribantumab in combination with paclitaxel in patients with advanced platinum-resistant or -refractory ovarian Cancer. J Clin Oncol. 2016;34(36):4345–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. McDonagh CF, et al. Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits Heregulin-induced activation of ErbB3. Mol Cancer Ther. 2012;11(3):582–93.

    Article  CAS  PubMed  Google Scholar 

  221. Okazaki S, et al. Development of an ErbB4 monoclonal antibody that blocks neuregulin-1-induced ErbB4 activation in cancer cells. Biochem Biophys Res Commun. 2016;470(1):239–44.

    Article  CAS  PubMed  Google Scholar 

  222. Lange T, et al. Trastuzumab has anti-metastatic and anti-angiogenic activity in a spontaneous metastasis xenograft model of esophageal adenocarcinoma. Cancer Lett. 2011;308(1):54–61.

    Article  CAS  PubMed  Google Scholar 

  223. Norman G, et al. Trastuzumab for the treatment of HER2-positive metastatic adenocarcinoma of the stomach or gastro-oesophageal junction. Health Technol Assess. 2011;15(Suppl_1):33–42.

    PubMed  Google Scholar 

  224. Slamon DJ, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast Cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–92.

    Article  CAS  PubMed  Google Scholar 

  225. Bang Y-J, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97.

    Article  CAS  PubMed  Google Scholar 

  226. Kondo N, et al. Antitumor effect of gefitinib on head and neck squamous cell carcinoma enhanced by trastuzumab. Oncol Rep. 2008;20(2):373–8.

    CAS  PubMed  Google Scholar 

  227. Kondo N, et al. Combined molecular targeted drug therapy for EGFR and HER-2 in head and neck squamous cell carcinoma cell lines. Int J Oncol. 2012;40(6):1805–12.

    CAS  PubMed  Google Scholar 

  228. Wilson TR, et al. Neuregulin-1-mediated autocrine signaling underlies sensitivity to HER2 kinase inhibitors in a subset of human cancers. Cancer Cell. 2011;20(2):158–72.

    Article  CAS  PubMed  Google Scholar 

  229. Kulkarni S, et al. TMEM16A/ANO1 suppression improves response to antibody mediated targeted therapy of EGFR and HER2/ERBB2. Genes Chromosom Cancer. 2017;56:460–71.

    Article  CAS  PubMed  Google Scholar 

  230. Fayette J, et al. Randomized phase II study of Duligotuzumab (MEHD7945A) vs. Cetuximab in squamous cell carcinoma of the head and neck (MEHGAN study). Front Oncol. 2016;6:232.

    Article  PubMed  PubMed Central  Google Scholar 

  231. Jimeno A, et al. Phase Ib study of duligotuzumab (MEHD7945A) plus cisplatin/5-fluorouracil or carboplatin/paclitaxel for first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck. Cancer. 2016;122(24):3803–11.

    Article  CAS  PubMed  Google Scholar 

  232. Juric D, et al. Safety and pharmacokinetics/pharmacodynamics of the first-in-class dual action HER3/EGFR antibody MEHD7945A in locally advanced or metastatic epithelial tumors. Clin Cancer Res. 2015;21(11):2462–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  233. Lee S, et al. Inhibition of ErbB3 by a monoclonal antibody that locks the extracellular domain in an inactive configuration. Proc Natl Acad Sci U S A. 2015;112(43):13225–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  234. Brand TM, et al. Human papillomavirus regulates HER3 expression in head and neck Cancer: implications for targeted HER3 therapy in HPV+ patients. Clin Cancer Res. 2017;23(12):3072–83.

    Article  CAS  PubMed  Google Scholar 

  235. Cohen EEW, et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol. 2003;21(10):1980–7.

    Article  CAS  PubMed  Google Scholar 

  236. Cohen EEW. Phase II trial of Gefitinib 250 mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res. 2005;11(23):8418–24.

    Article  CAS  PubMed  Google Scholar 

  237. Caponigro F, et al. A phase I/II trial of gefitinib and radiotherapy in patients with locally advanced inoperable squamous cell carcinoma of the head and neck. Anti-Cancer Drugs. 2008;19(7):739–44.

    Article  CAS  PubMed  Google Scholar 

  238. Hainsworth JD, et al. Neoadjuvant chemotherapy/gefitinib followed by concurrent chemotherapy/radiation therapy/gefitinib for patients with locally advanced squamous carcinoma of the head and neck. Cancer. 2009;115(10):2138–46.

    Article  CAS  PubMed  Google Scholar 

  239. Stewart JSW, et al. Phase III study of Gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2009;27(11):1864–71.

    Article  CAS  PubMed  Google Scholar 

  240. Baselga J, et al. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol. 2002;20(21):4292–302.

    Article  CAS  PubMed  Google Scholar 

  241. Perez CA, et al. Phase II study of gefitinib adaptive dose escalation to skin toxicity in recurrent or metastatic squamous cell carcinoma of the head and neck. Oral Oncol. 2012;48(9):887–92.

    Article  CAS  PubMed  Google Scholar 

  242. Argiris A, et al. Phase III randomized, placebo-controlled trial of docetaxel with or without Gefitinib in recurrent or metastatic head and neck Cancer: an eastern cooperative oncology group trial. J Clin Oncol. 2013;31(11):1405–14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  243. Chen L, et al. Predictive factors associated with gefitinib response in patients with advanced non-small-cell lung cancer (NSCLC). Chin J Cancer Res. 2014;26(4):466–70.

    PubMed  PubMed Central  Google Scholar 

  244. Scheffler M, et al. Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on 4-anilinoquinazolines. Clin Pharmacokinet. 2011;50(6):371–403.

    Article  CAS  PubMed  Google Scholar 

  245. Swaisland HC, et al. Single-dose clinical pharmacokinetic studies of gefitinib. Clin Pharmacokinet. 2005;44(11):1165–77.

    Article  CAS  PubMed  Google Scholar 

  246. Siu LL, et al. Phase I/II trial of Erlotinib and cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Princess Margaret Hospital phase II consortium and National Cancer Institute of Canada clinical trials group study. J Clin Oncol. 2007;25(16):2178–83.

    Google Scholar 

  247. Hamilton M, et al. Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res. 2006;12(7 Pt 1):2166–71.

    Article  CAS  PubMed  Google Scholar 

  248. Xia W, et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene. 2002;21(41):6255–63.

    Article  CAS  PubMed  Google Scholar 

  249. de Souza JA, 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  PubMed  PubMed Central  CAS  Google Scholar 

  250. Harrington K, et al. Postoperative adjuvant Lapatinib and concurrent Chemoradiotherapy followed by maintenance Lapatinib monotherapy in high-risk patients with resected squamous cell carcinoma of the head and neck: a phase III, randomized, double-blind, placebo-controlled study. J Clin Oncol. 2015;33(35):4202–9.

    Article  CAS  PubMed  Google Scholar 

  251. Sacco AG, Worden FP. Molecularly targeted therapy for the treatment of head and neck cancer: a review of the ErbB family inhibitors. OncoTargets and therapy. 2016;9:1927.

    PubMed  PubMed Central  CAS  Google Scholar 

  252. Solca F, et al. Target binding properties and cellular activity of Afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther. 2012;343(2):342–50.

    Article  CAS  PubMed  Google Scholar 

  253. Markovic A, Chung CH. Current role of EGF receptor monoclonal antibodies and tyrosine kinase inhibitors in the management of head and neck squamous cell carcinoma. Expert Rev Anticancer Ther. 2012;12(9):1149–59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  254. Machiels J-PH, et al. Activity of afatinib administered in a window pre-operative study in squamous cell carcinoma of the head and neck (SCCHN) : EORTC-90111. J Clin Oncol. 2016;34(15_suppl):6049–6049.

    Google Scholar 

  255. Cohen EEW, et al. Biomarker analysis in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients (pts) treated with second-line afatinib versus methotrexate (MTX): LUX-Head & Neck 1 (LUX-H&N1). J Clin Oncol. 2015;33(15_suppl):6023–6023.

    Google Scholar 

  256. Burtness B, et al. LUX-head and neck 2: randomized, double-blind, placebo-controlled, phase III trial of afatinib as adjuvant therapy after chemoradiation (CRT) in primary unresected, high/intermediate-risk, squamous cell cancer of the head and neck (HNSCC) patients (pts). J Clin Oncol. 2017;35(15_suppl):6001–6001

    Google Scholar 

  257. Kalous O, et al. Dacomitinib (PF-00299804), an irreversible pan-HER inhibitor, inhibits proliferation of HER2-amplified breast Cancer cell lines resistant to Trastuzumab and Lapatinib. Mol Cancer Ther. 2012;11(9):1978–87.

    Article  CAS  PubMed  Google Scholar 

  258. Engelman JA, et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung Cancer models with EGFR and ERBB2 mutations that are resistant to Gefitinib. Cancer Res. 2007;67(24):11924–32.

    Article  CAS  PubMed  Google Scholar 

  259. Williams JP, et al. Pre-clinical characterization of Dacomitinib (PF-00299804), an irreversible pan-ErbB inhibitor, combined with ionizing radiation for head and neck squamous cell carcinoma. PLoS One. 2014;9(5):e98557.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  260. Chiu JW, et al. Pharmacokinetic assessment of dacomitinib (pan-HER tyrosine kinase inhibitor) in patients with locally advanced head and neck squamous cell carcinoma (LA SCCHN) following administration through a gastrostomy feeding tube (GT). Investig New Drugs. 2015;33(4):895–900.

    Article  CAS  Google Scholar 

  261. Audet M-L, et al. Evaluation of potential predictive markers of efficacy of dacomitinib in patients (pts) with recurrent/metastatic SCCHN from a phase II trial. J Clin Oncol. 2013;31(15_suppl):6041–6041.

    Google Scholar 

  262. Cai X, et al. Discovery of 7-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of Cancer. J Med Chem. 2010;53(5):2000–9.

    Article  CAS  PubMed  Google Scholar 

  263. Lai CJ, et al. CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity. Cancer Res. 2010;70(9):3647–56.

    Article  CAS  PubMed  Google Scholar 

  264. Galloway TJ, et al. A phase I study of CUDC-101, a multitarget inhibitor of HDACs, EGFR, and HER2, in combination with Chemoradiation in patients with head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21(7):1566–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Xie T, et al. Pharmacological targeting of the pseudokinase Her3. Nat Chem Biol. 2014;10(12):1006–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  266. Mizrachi A, et al. Tumour-specific PI3K inhibition via nanoparticle-targeted delivery in head and neck squamous cell carcinoma. Nat Commun. 2017;8:14292.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  267. Zumsteg ZS, et al. Taselisib (GDC-0032), a potent beta-sparing small molecule inhibitor of PI3K, Radiosensitizes head and neck squamous carcinomas containing activating PIK3CA alterations. Clin Cancer Res. 2016;22(8):2009–19.

    Article  CAS  PubMed  Google Scholar 

  268. Burris HA, 3rd, Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol. 2013;71(4):829–842.

    Google Scholar 

  269. Dolly SO, et al. Phase I study of Apitolisib (GDC-0980), dual Phosphatidylinositol-3-kinase and mammalian target of rapamycin kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2016;22(12):2874–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  270. Geiger JL, et al. Phase II trial of everolimus in patients with previously treated recurrent or metastatic head and neck squamous cell carcinoma. Head Neck. 2016;38(12):1759–64.

    Article  PubMed  PubMed Central  Google Scholar 

  271. Anisuzzaman AS, et al. In vitro and in vivo synergistic antitumor activity of the combination of BKM120 and erlotinib in head and neck cancer: mechanism of apoptosis and resistance. Mol Cancer Ther. 2017;16:729–38.

    Article  CAS  PubMed  Google Scholar 

  272. Rebucci M, et al. Mechanisms underlying resistance to cetuximab in the HNSCC cell line: role of AKT inhibition in bypassing this resistance. Int J Oncol. 2011;38(1):189–200.

    CAS  PubMed  Google Scholar 

  273. Mohan S, et al. MEK inhibitor PD-0325901 overcomes resistance to PI3K/mTOR inhibitor PF-5212384 and potentiates antitumor effects in human head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21(17):3946–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  274. Gonzales CB, et al. Co-targeting ALK and EGFR parallel signaling in oral squamous cell carcinoma. Oral Oncol. 2016;59:12–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  275. Zhou J, et al. CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma. Nat Commun. 2017;8:13897.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  276. Michel L, 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  PubMed  PubMed Central  CAS  Google Scholar 

  277. Zeng L, et al. Combining Chk1/2 inhibition with cetuximab and radiation enhances in vitro and in vivo cytotoxicity in head and neck squamous cell carcinoma. Mol Cancer Ther. 2017;16(4):591–600.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  278. Huang KK, et al. Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck. Sci Rep. 2016;6:19552.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  279. Koole K, et al. FGFR1 is a potential prognostic biomarker and therapeutic target in head and neck squamous cell carcinoma. Clin Cancer Res. 2016;22(15):3884–93.

    Article  CAS  PubMed  Google Scholar 

  280. Muntasell A, et al. Targeting NK-cell checkpoints for cancer immunotherapy. Curr Opin Immunol. 2017;45:73–81.

    Article  CAS  PubMed  Google Scholar 

  281. Srivastava RM, et al. CD137 stimulation enhances Cetuximab-induced natural killer: dendritic cell priming of antitumor T-cell immunity in patients with head and neck Cancer. Clin Cancer Res. 2017;23(3):707–16.

    Article  CAS  PubMed  Google Scholar 

  282. Luedke E, et al. Cetuximab therapy in head and neck cancer: immune modulation with interleukin-12 and other natural killer cell-activating cytokines. Surgery. 2012;152(3):431–40.

    Article  PubMed  Google Scholar 

  283. Kumai T, et al. Targeting HER-3 to elicit antitumor helper T cells against head and neck squamous cell carcinoma. Sci Rep. 2015;5:16280.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  284. Jie HB, et al. CTLA-4(+) regulatory T cells increased in Cetuximab-treated head and neck Cancer patients suppress NK cell cytotoxicity and correlate with poor prognosis. Cancer Res. 2015;75(11):2200–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  285. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  286. Lyford-Pike S, et al. Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013;73(6):1733–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  287. Concha-Benavente F, et al. Identification of the cell-intrinsic and -extrinsic pathways downstream of EGFR and IFNgamma that induce PD-L1 expression in head and neck Cancer. Cancer Res. 2016;76(5):1031–43.

    Article  PubMed  CAS  Google Scholar 

  288. Boeckx C, et al. Anti-epidermal growth factor receptor therapy in head and neck squamous cell carcinoma: focus on potential molecular mechanisms of drug resistance. Oncologist. 2013;18(7):850–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  289. Wheeler DL, et al. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene. 2008;27(28):3944–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  290. Wheeler DL, et al. Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximab. Cancer Biol Ther. 2009;8(8):696–703.

    Article  PubMed  CAS  Google Scholar 

  291. Lu Y, et al. Epidermal growth factor receptor (EGFR) ubiquitination as a mechanism of acquired resistance escaping treatment by the anti-EGFR monoclonal antibody Cetuximab. Cancer Res. 2007;67(17):8240–7.

    Article  CAS  PubMed  Google Scholar 

  292. P O-charoenrat, et al. Vascular endothelial growth factor family members are differentially regulated by c-erbB signaling in head and neck squamous carcinoma cells. Clin Exp Metastasis. 2000;18(2):155–61.

    Article  Google Scholar 

  293. Sen M, et al. Targeting Stat3 abrogates EGFR inhibitor resistance in Cancer. Clin Cancer Res. 2012;18(18):4986–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  294. Misale S, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486:532–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  295. Diaz LA Jr, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486(7404):537–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  296. Johansson AC, et al. Cancer-associated fibroblasts induce matrix metalloproteinase-mediated Cetuximab resistance in head and neck squamous cell carcinoma cells. Mol Cancer Res. 2012;10(9):1158–68.

    Article  CAS  PubMed  Google Scholar 

  297. Ogawa T, et al. Methylation of death-associated protein kinase is associated with cetuximab and erlotinib resistance. Cell Cycle. 2012;11(8):1656–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  298. Ahsan A, et al. Role of epidermal growth factor receptor degradation in cisplatin-induced cytotoxicity in head and neck cancer. Cancer Res. 2010;70(7):2862–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  299. Stoehlmacher-Williams J, et al. Polymorphisms of the epidermal growth factor receptor (EGFR) and survival in patients with advanced cancer of the head and neck (HNSCC). Anticancer Res. 2012;32(2):421–5.

    CAS  PubMed  Google Scholar 

  300. Wang Y, et al. A meta-analysis on the relations between EGFR R521K polymorphism and risk of Cancer. Int J Genomics. 2014;2014:1–7.

    Article  CAS  Google Scholar 

  301. Shinkawa T, et al. The absence of Fucose but not the presence of galactose or bisecting N-Acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem. 2002;278(5):3466–73.

    Article  CAS  PubMed  Google Scholar 

  302. Suzuki E, et al. A Nonfucosylated anti-HER2 antibody augments antibody-dependent cellular cytotoxicity in breast Cancer patients. Clin Cancer Res. 2007;13(6):1875–82.

    Article  CAS  PubMed  Google Scholar 

  303. Braig F, et al. Cetuximab resistance in head and neck cancer is mediated by EGFR-K521Polymorphism. Cancer Res. 2016;77(5):1188–99.

    Article  CAS  PubMed  Google Scholar 

  304. Ritter CA, et al. Human breast cancer cells selected for resistance to Trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res. 2007;13(16):4909–19.

    Article  CAS  PubMed  Google Scholar 

  305. Wang D, et al. HER3 targeting sensitizes HNSCC to Cetuximab by reducing HER3 activity and HER2/HER3 dimerization: evidence from cell line and patient-derived xenograft models. Clin Cancer Res. 2016;23(3):677–86.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  306. Cabebe E, Wakelee H. Role of anti-angiogenesis agents in treating NSCLC: focus on bevacizumab and VEGFR tyrosine kinase inhibitors. Curr Treat Options in Oncol. 2007;8(1):15–27.

    Article  Google Scholar 

  307. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8(8):579–91.

    Article  CAS  PubMed  Google Scholar 

  308. Ratushny V, et al. Targeting EGFR resistance networks in head and neck cancer. Cell Signal. 2009;21(8):1255–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  309. Seiwert TY, Cohen EEW. Targeting angiogenesis in head and neck cancer. Semin Oncol. 2008;35(3):274–85.

    Article  PubMed  Google Scholar 

  310. Liao YH, et al. Epidermal growth factor-induced ANGPTL4 enhances anoikis resistance and tumour metastasis in head and neck squamous cell carcinoma. Oncogene. 2017;36(16):2228–42.

    Article  CAS  PubMed  Google Scholar 

  311. Mayer A, et al. Downregulation of EGFR in hypoxic, diffusion-limited areas of squamous cell carcinomas of the head and neck. Br J Cancer. 2016;115(11):1351–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  312. Bossi P, et al. Functional genomics uncover the biology behind the responsiveness of head and neck squamous cell Cancer patients to Cetuximab. Clin Cancer Res. 2016;22(15):3961–70.

    Article  CAS  PubMed  Google Scholar 

  313. Riedel F, et al. EGFR antisense treatment of human HNSCC cell lines down-regulates VEGF expression and endothelial cell migration. Int J Oncol. 2002;21(1):11–6.

    CAS  PubMed  Google Scholar 

  314. Cohen EEW, et al. Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet Oncol. 2009;10(3):247–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  315. Soulieres D, et al. Multicenter phase II study of Erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell Cancer of the head and neck. J Clin Oncol. 2004;22(1):77–85.

    Article  CAS  PubMed  Google Scholar 

  316. Fury MG, et al. A phase II study of SU5416 in patients with advanced or recurrent head and neck cancers. Investig New Drugs. 2006;25(2):165–72.

    Article  CAS  Google Scholar 

  317. Elser C, et al. Phase II trial of Sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol. 2007;25(24):3766–73.

    Article  CAS  PubMed  Google Scholar 

  318. Gilbert J, et al. A randomized phase II efficacy and correlative studies of cetuximab with or without sorafenib in recurrent and/or metastatic head and neck squamous cell carcinoma. Oral Oncol. 2015;51(4):376–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  319. Argiris A, 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. 2012;24(1):220–5.

    Article  PubMed  PubMed Central  Google Scholar 

  320. Argiris A, et al. Phase II randomized trial of radiation therapy, cetuximab, and pemetrexed with or without bevacizumab in patients with locally advanced head and neck cancer. Ann Oncol. 2016;27(8):1594–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  321. Hurwitz SJ, et al. Pharmacodynamics of DT-IgG, a dual-targeting antibody against VEGF-EGFR, in tumor xenografted mice. Cancer Chemother Pharmacol. 2011;69(3):577–90.

    Article  CAS  PubMed  Google Scholar 

  322. Zhang H, et al. A dual-targeting antibody against EGFR-VEGF for lung and head and neck cancer treatment. Int J Cancer. 2011;131(4):956–69.

    Article  CAS  PubMed  Google Scholar 

  323. Lecaros RLG, et al. Nanoparticle delivered VEGF-A siRNA enhances photodynamic therapy for head and neck cancer treatment. Mol Ther. 2016;24(1):106–16.

    Article  CAS  PubMed  Google Scholar 

  324. Liu F-Y, et al. CCR7 regulates cell migration and invasion through JAK2/STAT3 in metastatic squamous cell carcinoma of the head and neck. Biomed Res Int. 2014;2014:1–11.

    CAS  Google Scholar 

  325. Karnoub AE, Weinberg RA. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol. 2008;9(7):517–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  326. Suda T, et al. Copy number amplification of the PIK3CA gene is associated with poor prognosis in non-lymph node metastatic head and neck squamous cell carcinoma. BMC Cancer. 2012;12:416.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  327. Smilek P, et al. Epidermal growth factor receptor (EGFR) expression and mutations in the EGFR signaling pathway in correlation with anti-EGFR therapy in head and neck squamous cell carcinomas. Neoplasma. 2012;59(05):508–15.

    Article  CAS  PubMed  Google Scholar 

  328. Braig F, et al. Liquid biopsy monitoring uncovers acquired RAS-mediated resistance to cetuximab in a substantial proportion of patients with head and neck squamous cell carcinoma. Oncotarget. 2016;7(28):42988–95.

    Article  PubMed  PubMed Central  Google Scholar 

  329. Rampias T, et al. RAS/PI3K crosstalk and cetuximab resistance in head and neck squamous cell carcinoma. Clin Cancer Res. 2014;20(11):2933–46.

    Article  CAS  PubMed  Google Scholar 

  330. Tinhofer I, et al. Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation. Eur J Cancer. 2016;57:78–86.

    Article  PubMed  CAS  Google Scholar 

  331. Pedrero JM, et al. Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma. Int J Cancer. 2005;114(2):242–8.

    Article  PubMed  CAS  Google Scholar 

  332. Lyu J, et al. Predictive value of pAKT/PTEN expression in oral squamous cell carcinoma treated with cetuximab-based chemotherapy. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;121(1):67–72.

    Article  PubMed  Google Scholar 

  333. Burtness B, et al. Activity of cetuximab (C) in head and neck squamous cell carcinoma (HNSCC) patients (pts) with PTEN loss or PIK3CA mutation treated on E5397, a phase III trial of cisplatin (CDDP) with placebo (P) or C. J Clin Oncol. 2013;31(15_suppl):6028–6028

    Google Scholar 

  334. McAllister SS, Weinberg RA. Tumor-host interactions: a far-reaching relationship. J Clin Oncol. 2010;28(26):4022–8.

    Article  PubMed  Google Scholar 

  335. Raudenska M, et al. Prognostic significance of the tumour-adjacent tissue in head and neck cancers. Tumour Biol. 2015;36(12):9929–39.

    Article  CAS  PubMed  Google Scholar 

  336. Baylin SB. Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet. 2001;10(7):687–92.

    Article  CAS  PubMed  Google Scholar 

  337. Chang X, et al. Identification of Hypermethylated genes associated with cisplatin resistance in human cancers. Cancer Res. 2010;70(7):2870–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  338. Gifford G. The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients. Clin Cancer Res. 2004;10(13):4420–6.

    Article  CAS  PubMed  Google Scholar 

  339. Segura-Pacheco B, et al. Global DNA hypermethylation-associated cancer chemotherapy resistance and its reversion with the demethylating agent hydralazine. J Transl Med. 2006;4:32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  340. Bedi A, et al. Inhibition of TGF-enhances the in vivo antitumor efficacy of EGF receptor-targeted therapy. Mol Cancer Ther. 2012;11(11):2429–39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  341. Hoellein A, 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 

  342. Astsaturov I, et al. Synthetic lethal screen of an EGFR-centered network to improve targeted therapies. Sci Signal. 2010;3(140):ra67-ra67.

    Google Scholar 

  343. Yuan L, et al. Recurrent FGFR3-TACC3 fusion gene in nasopharyngeal carcinoma. Cancer Biol Ther. 2014;15(12):1613–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  344. Daly C, et al. FGFR3-TACC3 fusion proteins act as naturally occurring drivers of tumor resistance by functionally substituting for EGFR/ERK signaling. Oncogene. 2017;36(4):471–81.

    Article  CAS  PubMed  Google Scholar 

  345. Burtness B, et al. NCCN task force report: management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. J Natl Compr Cancer Netw. 2009;7(Suppl 1):S5–21. quiz S22-4

    Article  Google Scholar 

  346. Fernandez-Mateos J, et al. Epidermal growth factor receptor (EGFR) pathway polymorphisms as predictive markers of cetuximab toxicity in locally advanced head and neck squamous cell carcinoma (HNSCC) in a Spanish population. Oral Oncol. 2016;63:38–43.

    Article  CAS  PubMed  Google Scholar 

  347. O’Neil BH, et al. High incidence of Cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. J Clin Oncol. 2007;25(24):3644–8.

    Article  PubMed  Google Scholar 

  348. Baas JM, et al. Recommendations on management of EGFR inhibitor-induced skin toxicity: a systematic review. Cancer Treat Rev. 2012;38(5):505–14.

    Article  CAS  PubMed  Google Scholar 

  349. Kohl P, et al. Systems biology: an approach. Clinical Pharmacology & Therapeutics. 2010;88(1):25–33.

    Article  CAS  Google Scholar 

  350. Chow YP, et al. Exome sequencing identifies potentially Druggable mutations in nasopharyngeal carcinoma. Sci Rep. 2017;7:42980.

    Article  PubMed  PubMed Central  Google Scholar 

  351. William WN, et al. Erlotinib and the risk of oral cancer: the erlotinib prevention of oral cancer (epoc) randomized clinical trial. JAMA Oncol. 2016;2(2):209–16.

    Article  PubMed  PubMed Central  Google Scholar 

  352. Khan Z, et al. Cetuximab activity in dysplastic lesions of the upper aerodigestive tract. Oral Oncol. 2016;53:60–6.

    Article  CAS  PubMed  Google Scholar 

  353. Ariotti N, et al. Epidermal growth factor receptor activation remodels the plasma membrane lipid environment to induce nanocluster formation. Mol Cell Biol. 2010;30(15):3795–804.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  354. Clayton AH, et al. Ligand-induced dimer-tetramer transition during the activation of the cell surface epidermal growth factor receptor—a multidimensional microscopy analysis. J Biol Chem. 2005;280(34):30392–9.

    Article  CAS  PubMed  Google Scholar 

  355. Needham SR, et al. EGFR oligomerization organizes kinase-active dimers into competent signalling platforms. Nat Commun. 2016;7:13307.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  356. Ramirez UD, et al. Compounds identified by virtual docking to a tetrameric EGFR extracellular domain can modulate Grb2 internalization. BMC Cancer. 2015;15:436.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  357. Ferris RL, et al. Phase II trial of post-operative radiotherapy with concurrent cisplatin plus panitumumab in patients with high-risk, resected head and neck cancer. Ann Oncol. 2016;27(12):2257–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  358. Machiels J-P, et al. Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial. Lancet Oncol. 2011;12(4):333–43.

    Article  CAS  PubMed  Google Scholar 

  359. Rodriguez MO, et al. Nimotuzumab plus radiotherapy for unresectable squamous-cell carcinoma of the head and neck. Cancer Biol Ther. 2010;9(5):343–9.

    Article  CAS  PubMed  Google Scholar 

  360. Reddy BK, et al. Nimotuzumab provides survival benefit to patients with inoperable advanced squamous cell carcinoma of the head and neck: a randomized, open-label, phase IIb, 5-year study in Indian patients. Oral Oncol. 2014;50(5):498–505.

    Article  CAS  PubMed  Google Scholar 

  361. Rao S, et al. Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer. Br J Cancer. 2008;99(6):868–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  362. Rao S, et al. Matuzumab plus epirubicin, cisplatin and capecitabine (ECX) compared with epirubicin, cisplatin and capecitabine alone as first-line treatment in patients with advanced oesophago-gastric cancer: a randomised, multicentre open-label phase II study. Ann Oncol. 2010;21(11):2213–9.

    Article  CAS  PubMed  Google Scholar 

  363. Martins RG, et al. Cisplatin and radiotherapy with or without Erlotinib in locally advanced squamous cell carcinoma of the head and neck: a randomized phase II trial. J Clin Oncol. 2013;31(11):1415–21.

    Article  CAS  PubMed  Google Scholar 

  364. Yao M, et al. Phase II study of erlotinib and docetaxel with concurrent intensity-modulated radiotherapy in locally advanced head and neck squamous cell carcinoma. Head Neck. 2016;38(Suppl 1):E1770–6.

    Article  PubMed  PubMed Central  Google Scholar 

  365. Harrington KJ, et al. Final analysis: a randomized, blinded, placebo (P)-controlled phase III study of adjuvant postoperative lapatinib (L) with concurrent chemotherapy and radiation therapy (CH-RT) in high-risk patients with squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol 2014;32(15_suppl):6005–6005

    Google Scholar 

  366. Huo ZJ, et al. Novel nanosystem to enhance the antitumor activity of lapatinib in breast cancer treatment: therapeutic efficacy evaluation. Cancer Sci. 2015;106(10):1429–37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  367. Machiels JP, 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 

  368. Abdul Razak AR, et al. A phase II trial of dacomitinib, an oral pan-human EGF receptor (HER) inhibitor, as first-line treatment in recurrent and/or metastatic squamous-cell carcinoma of the head and neck. Ann Oncol. 2012;24(3):761–9.

    Article  PubMed  Google Scholar 

  369. Kim HS, et al. Phase II clinical and exploratory biomarker study of dacomitinib in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Clin Cancer Res. 2015;21(3):544–52.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors were supported by R21CA191425 and R01DK108195 (to EAG), Ruth L. Kirschstein National Research Service Award F30 Fellowship (F30 CA180607 to TNB), and NIH core grant CA06927 (to Fox Chase Cancer Center).

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Authors and Affiliations

  1. Department of Biochemistry and Biotechnology, Kazan Federal University, Kazan, Tatarstan, Russia

    Anna Kiseleva

  2. Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA

    Anna Kiseleva, Tim N. Beck, Ilya G. Serebriiskii & Erica A. Golemis

  3. Program in Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA, USA

    Tim N. Beck

  4. School of Pharmacy, Jiangsu University, Jiangsu Sheng, China

    Hanqing Liu

  5. Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA

    Barbara Burtness

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  2. Tim N. Beck
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  3. Ilya G. Serebriiskii
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  4. Hanqing Liu
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  5. Barbara Burtness
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  6. Erica A. Golemis
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Corresponding author

Correspondence to Erica A. Golemis .

Editor information

Editors and Affiliations

  1. Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Barbara Burtness

  2. Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

    Erica A. Golemis

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Kiseleva, A., Beck, T.N., Serebriiskii, I.G., Liu, H., Burtness, B., Golemis, E.A. (2018). Targeting the ErbB Family in Head and Neck Cancer. In: Burtness, B., Golemis, E. (eds) Molecular Determinants of Head and Neck Cancer. Current Cancer Research. Humana Press, Cham. https://doi.org/10.1007/978-3-319-78762-6_2

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  • DOI: https://doi.org/10.1007/978-3-319-78762-6_2

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  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-78761-9

  • Online ISBN: 978-3-319-78762-6

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