Seminars in Oncology
Volume 31, Issue 6 , Pages 734-743 , December 2004

The epidermal growth factor receptor signaling network in head and neck carcinogenesis and implications for targeted therapy

  • Rebecca G. Pomerantz

      Affiliations

    • Department of Otolaryngology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA
    • ,
  • Jennifer Rubin Grandis

      Affiliations

    • Department of Otolaryngology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA
    • Corresponding Author InformationAddress reprint requests to Jennifer Rubin Grandis, MD, 200 Lothrop St, Suite 500, Pittsburgh, PA, 15213

References 

  1. Bromberg J , Darnell JE . The role of STATs in transcriptional control and their impact on cellular function . Oncogene . 2000;19:2468–2473
  2. Song JI , Grandis JR . STAT signaling in head and neck cancer . Oncogene . 2000;19:2489–2495
  3. Grandis JR , Drenning SD , Zeng Q , et al.   Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo . Proc Natl Acad Sci U S A . 2000;97:4227–4232
  4. Leong PL , Xi S , Drenning SD , et al.   Differential function of STAT5 isoforms in head and neck cancer growth control . Oncogene . 2002;21:2846–2853
  5. Chen H , Lee JM , Zong Y , et al.   Linkage between STAT regulation and Epstein-Barr virus gene expression in tumors . J Virol . 2001;75:2929–2937
  6. Kazansky AV , Rosen JM . Signal transducers and activators of transcription 5B potentiates v-Src-mediated transformation of NIH-3T3 cells . Cell Growth Differ . 2001;12:1–7
  7. Srinivasan M , Jewell SD . Evaluation of TGF-alpha and EGFR expression in oral leukoplakia and oral submucous fibrosis by quantitative immunohistochemistry . Oncology . 2001;61:284–292
  8. Rubin Grandis J , Tweardy DJ , Melhem MF . Asynchronous modulation of transforming growth factor alpha and epidermal growth factor receptor protein expression in progression of premalignant lesions to head and neck squamous cell carcinoma . Clin Cancer Res . 1998;4:13–20
  9. Shin DM , Ro JY , Hong WK , et al.   Dysregulation of epidermal growth factor receptor expression in premalignant lesions during head and neck tumorigenesis . Cancer Res . 1994;54:3153–3159
  10. van Oijen MG , Rijksen G , ten Broek FW , et al.   Increased expression of epidermal growth factor receptor in normal epithelium adjacent to head and neck carcinomas independent of tobacco and alcohol abuse . Oral Dis . 1998;4:4–8
  11. Bei R , Pompa G , Vitolo D , et al.   Co-localization of multiple ErbB receptors in stratified epithelium of oral squamous cell carcinoma . J Pathol . 2001;195:343–348
  12. Nagatsuka H , Ishiwari Y , Tsujigiwa H , et al.   Quantitation of epidermal growth factor receptor gene amplification by competitive polymerase chain reaction in pre-malignant and malignant oral epithelial lesions . Oral Oncol . 2001;37:599–604
  13. Rodrigo JP , Gonzalez MV , Lazo PS , et al.   Genetic alterations in squamous cell carcinomas of the hypopharynx with correlations to clinicopathological features . Oral Oncol . 2002;38:357–363
  14. Freier K , Joos S , Flechtenmacher C , et al.   Tissue microarray analysis reveals site-specific prevalence of oncogene amplifications in head and neck squamous cell carcinoma . Cancer Res . 2003;63:1179–1182
  15. Mischel PS , Cloughesy TF . Targeted molecular therapy of GBM . Brain Pathol . 2003;13:52–61
  16. Seth D , Shaw K , Jazayeri J , et al.   Complex post-transcriptional regulation of EGF-receptor expression by EGF and TGF-alpha in human prostate cancer cells . Br J Cancer . 1999;80:657–669
  17. Rubin Grandis J , Zeng Q , Tweardy DJ . Retinoic acid normalizes the increased gene transcription rate of TGF-alpha and EGFR in head and neck cancer cell lines . Nat Med . 1996;2:237–240
  18. Bankfalvi A , Krassort M , Vegh A , et al.   Deranged expression of the E-cadherin/beta-catenin complex and the epidermal growth factor receptor in the clinical evolution and progression of oral squamous cell carcinomas . J Oral Pathol Med . 2002;31:450–457
  19. Chang JL , Tsao YP , Liu DW , et al.   The expression of type I growth factor receptors in the squamous neoplastic changes of uterine cervix . Gynecol Oncol . 1999;73:62–71
  20. Leav I , McNeal JE , Ziar J , et al.   The localization of transforming growth factor alpha and epidermal growth factor receptor in stromal and epithelial compartments of developing human prostate and hyperplastic, dysplastic, and carcinomatous lesions . Hum Pathol . 1998;29:668–675
  21. Lorimer IA . Mutant epidermal growth factor receptors as targets for cancer therapy . Curr Cancer Drug Targets . 2002;2:91–102
  22. Khalil MY , Grandis JR , Shin DM . Targeting epidermal growth factor receptor (novel therapeutics in the management of cancer) . Expert Rev Anticancer Ther . 2003;3:367–380
  23. Rubin Grandis J , 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;53:3579–3584
  24. Chen BK , Ohtsuki Y , Furihata M , et al.   Co-overexpression of p53 protein and epidermal growth factor receptor in human papillary thyroid carcinomas correlated with lymph node metastasis, tumor size and clinicopathologic stage . Int J Oncol . 1999;15:893–898
  25. Ang KK , Berkey BA , Tu X , et al.   Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma . Cancer Res . 2002;62:7350–7356
  26. Etienne MC , Pivot X , Formento JL , et al.   A multifactorial approach including tumoural epidermal growth factor receptor, p53, thymidylate synthase and dihydropyrimidine dehydrogenase to predict treatment outcome in head and neck cancer patients receiving 5-fluorouracil . Br J Cancer . 1999;79:1864–1869
  27. Rubin Grandis J , Melhem MF , Gooding WE , et al.   Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival . J Natl Cancer Inst . 1998;90:824–832
  28. Numico G , Colantonio I , Comino A , et al.   EGFR and survival of patients with locally advanced head and neck cancer (HNC) and treated with alternating chemotherapy radiation (CT-RT). Results of a retrospective analysis . Proc Am Soc Clin Oncol . 2003;22:2018; (abstr 2018)
  29. Gupta AK , McKenna WG , Weber CN , et al.   Local recurrence in head and neck cancer (Relationship to radiation resistance and signal transduction) . Clin Cancer Res . 2002;8:885–892
  30. Razis E , Poapadopoulos S , Xilouri M , et al.   Evaluation of serum EGFR in head and neck cancer patients . Proc Am Soc Clin Oncol . 2003;22:515; (abstr 2073)
  31. Huang SM , Bock JM , Harari PM . Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck . Cancer Res . 1999;59:1935–1940
  32. Huang SM , Li J , Harari PM . Molecular inhibition of angiogenesis and metastatic potential in human squamous cell carcinomas after epidermal growth factor receptor blockade . Mol Cancer Ther . 2002;1:507–514
  33. Harari PM , Huang SM . Head and neck cancer as a clinical model for molecular targeting of therapy (Combining EGFR blockade with radiation) . Int J Radiat Oncol Biol Phys . 2001;49:427–433
  34. Milas L , Mason K , Hunter N , et al.   In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody . Clin Cancer Res . 2000;6:701–708
  35. Ciardiello F , Bianco R , Damiano V , et al.   Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225 . Clin Cancer Res . 1999;5:909–916
  36. Hong WK , Arquette M , Nabell L . Efficacy and safety of the anti-epidermal growth factor receptor antibody (EGFR) IMC-C225, in combination with cisplatin in patients with recurrent squamous cell carcinoma of the head and neck refractory to cisplatin containing chemotherapy . Proc Am Soc Clin Oncol . 2001;20:224a; (abstr)
  37. Shin DM , Donato NJ , Perez-Soler R , et al.   Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer . Clin Cancer Res . 2001;7:1204–1213
  38. Robert F , Ezekiel MP , Spencer SA , 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;19:3234–3243
  39. Chan AT , Hsu MM , Goh BC , et al.   A phase II study of cetuximab (C225) in combination with carboplatin patients (pts) with recurrent or metastatic nasopharyngeal carcinoma (NPC) who failed to a platinum-based chemotherapy . Proc Am Soc Clin Oncol . 2003;22:2000; (abstr)
  40. Vega-Villegas E , Awada A , Mesia R , et al.   A phase I study of cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil (5=FU) in patients (pts) with recurrent or metastatic squamous cell carcinoma of the head and neck (R&M SCCHN) . Proc Am Soc Clin Oncol . 2003;22:202; (abstr)
  41. Pfister DG , Aliff TB , Kraus DH , et al.   Concurrent cetuximab, cisplatin, and concomitant boost radiation therapy for locoregionally advanced, squamous cell head and neck cancer (SCCHN) (Preliminary evaluation of a new combined-modality paradigm) . Proc Am Soc Clin Oncol . 2003;22:1993; (abstr)
  42. Rubin Grandis J , Chakraborty A , Melhem MF , et al.   Inhibition of epidermal growth factor receptor gene expression and function decreases proliferation of head and neck squamous carcinoma but not normal mucosal epithelial cells . Oncogene . 1997;15:409–416
  43. Hoffmann T , Hafner D , Ballo H , et al.   Antitumor activity of anti-epidermal growth factor receptor monoclonal antibodies and cisplatin in ten human head and neck squamous cell carcinoma lines . Anticancer Res . 1997;17:4419–4425
  44. van Gog FB , Brakenhoff RH , Stigter-van Walsum M , et al.   Perspectives of combined radioimmunotherapy and anti-EGFR antibody therapy for the treatment of residual head and neck cancer . Int J Cancer . 1998;77:13–18
  45. Bier H , Reiffen KA , Haas I , et al.   Dose-dependent access of murine anti-epidermal growth factor receptor monoclonal antibody to tumor cells in patients with advanced laryngeal and hypopharyngeal carcinoma . Eur Arch Otorhinolaryngol . 1995;252:433–439
  46. Bier H , Hoffmann T , Hauser U , et al.   Clinical trial with escalating doses of the antiepidermal growth factor receptor humanized monoclonal antibody EMD 72 000 in patients with advanced squamous cell carcinoma of the larynx and hypopharynx . Cancer Chemother Pharmacol . 2001;47:519–524
  47. Tewes M , Schleucher N , Dirsch O , et al.   Results of a phase I trial of the humanized anti epidermal growth factor receptor (EGFR) monoclonal antibody EMD 72000 in patients with EGFR expressing solid tumors . Proc Am Soc Clin Oncol . 2002;21:37; (abstr)
  48. Crombet T , Osorio M , Cruz T , et al.   Use of the anti-EGFR antibody h-R3 in combination with radiotherapy in the treatment of advanced head and neck cancer . Proc Am Soc Clin Oncol. . 2002;21:14a; (abstr)
  49. Winquist E , Nabid A , Sicheri D , et al.   A phase I dose escalation study of a humanized monoclonal antibody to EGFR (hR3) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) treated with radiotherapy (RT) . Proc Am Soc Clin Oncol . 2002;21:926; (abstr)
  50. Yang XD , Jia XC , Corvalan JR , et al.   Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy . Cancer Res . 1999;59:1236–1243
  51. Figlin RA , Belldegrun A , Lohner ME , et al.   ABX-EGF (A fully humanized antiEGF receptor antibody in patients with advanced cancer) . Proc Am Soc Clin Oncol . 2001;20:1102; (abstr)
  52. Schwartz G , Dutcher JP , Vogelzang NJ , et al.   Phase 2 clinical trial evaluating the safety and effectiveness of ABX-EGF in renal cell cancer (RCC) . Proc Am Soc Clin Oncol . 2002;21:91; (abstr)
  53. Azemar M , Schmidt M , Arlt F , et al.   Recombinant antibody toxins specific for ErbB2 and EGF receptor inhibit the in vitro growth of human head and neck cancer cells and cause rapid tumor regression in vivo . Int J Cancer . 2000;86:269–275
  54. Schmidt M , Wels W . Targeted inhibition of tumour cell growth by a bispecific single-chain toxin containing an antibody domain and TGF alpha . Br J Cancer . 1996;74:853–862
  55. Schumann J , Angermuller S , Bang R , et al.   Acute hepatotoxicity of Pseudomonas aeruginosa exotoxin A in mice depends on T cells and TNF . J Immunol . 1998;161:5745–5754
  56. Sampson JH , Reardon DB , Akabani G , et al.   A phase I study of intratumoral infusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-α and a mutated form of the pseudomonas exotoxin (TP-38) for the treatment of malignant brain tumors . Proc Am Soc Clin Oncol . 2002;21:1860; (abstr)
  57. Goldberg MR , Heimbrook DC , Russo P , et al.   Phase I clinical study of the recombinant oncotoxin TP40 in superficial bladder cancer . Clin Cancer Res . 1995;1:57–61
  58. Cohen MH , Williams GA , Sridhara R , et al.   FDA drug approval summary (Gefitinib (ZD1839) (Iressa) tablets) . Oncologist . 2003;8:303–306
  59. Magne N , Fischel JL , Dubreuil A , et al.   Influence of epidermal growth factor receptor (EGFR), p53 and intrinsic MAP kinase pathway status of tumour cells on the antiproliferative effect of ZD1839 (“Iressa”) . Br J Cancer . 2002;86:1518–1523
  60. Moasser MM , Basso A , Averbuch SD , et al.   The tyrosine kinase inhibitor ZD1839 (“Iressa”) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells . Cancer Res . 2001;61:7184–7188
  61. Magne N , Fischel JL , Dubreuil A , et al.   Sequence-dependent effects of ZD1839 (’Iressa’) in combination with cytotoxic treatment in human head and neck cancer . Br J Cancer . 2002;86:819–827
  62. Huang SM , Li J , Armstrong EA , et al.   Modulation of radiation response and tumor-induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 (Iressa) . Cancer Res . 2002;62:4300–4306
  63. Baselga J , Rischin D , Ranson M , 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;20:4292–4302
  64. Herbst RS , Maddox AM , Rothenberg ML , et al.   Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors (Results of a phase I trial) . J Clin Oncol . 2002;20:3815–3825
  65. Cohen EE , Rosen F , Stadler WM , et al.   Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck . J Clin Oncol . 2003;21:1980–1987
  66. Cohen EEW , Stenson K , Gustin DM . A phase II study of 250 mg gefitinib (ZD1839) monotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) . Proc Am Soc Clin Oncol . 2003;22:202; (abstr)
  67. Akita RW , Sliwkowski MX . Preclinical studies with Erlotinib (Tarceva) . Semin Oncol . 2003;30:15–24
  68. Hidalgo M , Siu LL , Nemunaitis J , et al.   Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies . J Clin Oncol . 2001;19:3267–3279
  69. Desai AA , Janisch L , George CM , et al.   Phase I and pharmacokinetic study of erlotonib HCL (E;OSI-774) in combination with capecitabine (C) in patients with advanced solid tumors . Proc Am Soc Clin Oncol . 2003;22:900; (abstr)
  70. Senzer NN , Soulieres D , Siu LL , et al.   Phase 2 evaluation of OSI-774, a potent oral antagonist of the EGFR-TK in patients with advanced squamous cell carcinoma of the head and neck . Chicago, IL: American Society of Clinical Oncology; 2003; May 31–June 3
  71. Clark GM , Perez-Soler R , Siu LL , et al.   Rash severity is predictive of increased survival in erlotinib HCI . Proc Am Soc Clin Oncol . 2003;22:786; (abstr)
  72. Murren JR , Papadimitrakopoulou VA , Sizer KC , et al.   A phase I dose-escalating study to evaluate the biological activity and parmacokinetics of PK1166, a novel tyrosine kinase inhibitor, in patients with advanced cancers . Proc Am Soc Clin Oncol . 2002;21:377; 95a (abstr)
  73. Xia W , Mullin RJ , Keith BR , 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;21:6255–6263
  74. Mullin RJ , Keith BR , Murray DM , et al.   Combination therapy with the dual EGFR-ERBB-2 tyrosine kinase inhibitor GW572016 . Proc Am Soc Clin Oncol . 2003;22:970; (abstr)
  75. Burris HA , Taylor C , Jones S , et al.   A phase I study of GW752016 in patients with solid tumors . Proc Am Soc Clin Oncol . 2003;22:994; (abstr)
  76. Gieseg MA , de Bock C , Ferguson LR , et al.   Evidence for epidermal growth factor receptor-enhanced chemosensitivity in combinations of cisplatin and the new irreversible tyrosine kinase inhibitor CI-1033 . Anticancer Drugs . 2001;12:683–690
  77. Smaill JB , Rewcastle GW , Loo JA , et al.   Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions . J Med Chem . 2000;43:1380–1397
  78. Nemunaitis JJ , Eiseman I , Cunningham CC , et al.   A phase I trial of CI-1033, a pan-erbB tyrosine kinase inhibitor, given daily for 14 days every 3 weeks, in patients with advanced solid tumors . Proc Am Soc Clin Oncol . 2003;22:974; (abstr)
  79. He Y , Zeng Q , Drenning SD , et al.   Inhibition of human squamous cell carcinoma growth in vivo by epidermal growth factor receptor antisense RNA transcribed from the U6 promoter . J Natl Cancer Inst . 1998;90:1080–1087
  80. Endo S , Zeng Q , Burke NA , et al.   TGF-alpha antisense gene therapy inhibits head and neck squamous cell carcinoma growth in vivo . Gene Ther . 2000;7:1906–1914
  81. Rubin Grandis J , Drenning SD , Zeng Q , et al.   Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo . Proc Natl Acad Sci U S A . 2000;97:4227–4232
  82. Riedel F , Gotte K , Li M , et al.   Abrogation of VEGF expression in human head and neck squamous cell carcinoma decreases angiogenic activity in vitro and in vivo . Int J Oncol . 2003;23:577–583
  83. Li M , Ye C , Feng C , et al.   Enhanced antiangiogenic therapy of squamous cell carcinoma by combined endostatin and epidermal growth factor receptor-antisense therapy . Clin Cancer Res . 2002;8:3570–3578
  84. Robert F , Ezekiel MP , Spencer SA , 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;19:3234–3243
  85. Pfister DG , Aliff TB , Kraus DH , et al.   Concurrent cetuximab, cisplatin, and concomitant boost radiation therapy for locoregionally advanced, squamous cell head and neck cancer (SCCHN) (Preliminary evaluation of a new combined-modality paradigm) . Proc Am Soc Clin Oncol . 2003;22:495; (abstr 1993)
  86. Cohen E , Rosen F , Dekker A , et al.   Phase II study of ZD1839 (Iressa) in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) . Proc Am Soc Clin Oncol . 2002;21:225a; (abstr)

 Supported in part by National Institutes of Health Grant No. RO1 CA77308-01 (to J.R.G.).

PII: S0093-7754(04)00412-9

doi: 10.1053/j.seminoncol.2004.09.015

Seminars in Oncology
Volume 31, Issue 6 , Pages 734-743 , December 2004

Article Tools

* Image Usage & Resolution