Skip to main content
PMC home page
Cancer Science logoLink to Cancer Science
. 2005 Aug 19;94(1):50–56. doi: 10.1111/j.1349-7006.2003.tb01351.x

Expression of constitutively activated EGFRvlll in non‐small cell lung cancer

Isamu Okamoto 1,3, Lawrence C Kenyon 2, David R Emlet 1, Takeshi Mori 4, Ji‐ichiro Sasaki 3, Susumu Hirosako 3, Yasuko Ichikawa 3, Hiroto Kishi 3, Andrew K Godwin 5, Masakazu Yoshioka 4, Moritaka Suga 3, Mitsuhiro Matsumoto 3, Albert J Wong 1,6
PMCID: PMC11160145  PMID: 12708474

Abstract

The epidermal growth factor receptor (EGFR) variant type III (variously called EGFRvlll, de2–7 EGFR or ΔGFR) has an in‐frame deletion of the extracellular domain and is found in numerous types of human tumors. Since EGFRvlll has been reported to be tumorspecific and has oncogenic potential, it is being investigated as a potential therapeutic target. Because the cell‐specific expression of EGFRvlll in lung has not been well documented, we examined the expression of EGFRvlll in 76 non‐small cell lung cancers (NSCLCs) and 10 non‐neoplastic lung tissues by immunohistochemistry using a new monoclonal antibody specific for this variant receptor. We found a higher incidence (30 of 76, 39%) of enhanced EGFRvlll expression in NSCLC than previously described. Interestingly, the presence of EGFRvlll was also observed in several normal tissue components of lung (e.g., normal bronchial epithelium). Given the high prevalence of EGFRvlll in NSCLC, a newly developed phospho‐specific (activated) EGFR antibody was employed for immunohistochemical analysis that permitted visualization of activated EGFR and/or EGFRvlll in tumors. This study presents evidence, for the first time, that EGFRvlll expressed in human tumors is phosphorylated and hence activated. Our results suggest that the sustained activation of EGFRvlll is implicated in the pathogenesis of NSCLC and thus EGFRvlll is a potential therapeutic target in this challenging disease. (Cancer Sci 2003; 94: 50–56)

References

  • 1. Thompson DM, Gill GN. The EGF receptor; structure, regulation and potential role in malignancy. Cancer Surv 1985; 4: 767–88. [PubMed] [Google Scholar]
  • 2. Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, Whittle N, Waterfield MD, Ullrich A, Schlessinger J. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 1985; 313: 144–7. [DOI] [PubMed] [Google Scholar]
  • 3. Wong AJ, Bigner SH, Bigner DD, Kinzler KW, Hamilton SR, Vogelstein B. Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci USA 1987; 84: 6899–903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Sobol RE, Astarita RW, Hofeditz C, Masui H, Fairshter R, Royston I, Mendelsohn J. Epidermal growth factor receptor expression in human lung carcinomas defined by a monoclonal antibody. J Natl Cancer Inst 1987; 79: 403–7. [PubMed] [Google Scholar]
  • 5. Harris AL, Nicholson S, Sainsbury R, Wright C, Farndon J. Epidermal growth factor receptor and other oncogenes as prognostic markers. J Natl Cancer Inst 1992; 11: 181–7. [PubMed] [Google Scholar]
  • 6. Grandis JR, Melhem MF, Gooding WE, Day R, Hoist VA, Wagener MM, Drenning SD, Tweardy DJ. Levels of TGF‐alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 1998; 90: 824–32. [DOI] [PubMed] [Google Scholar]
  • 7. Di Fiore PP, Pierce JH, Fleming TP, Kazan R, Ullrich A, King CR, Schlessinger J, Aaronson SA. Overexpression of the human EGF receptor confers an EGF‐dependent transformed phenotype to NIH 3T3 cells. Cell 1987; 51: 1063–70. [DOI] [PubMed] [Google Scholar]
  • 8. Velu TJ, Beguinot L, Vass WC, Willingham MC, Merlino GT, Pastan I, Lowy DR. Epidermal‐growth‐factor‐dependent transformation by a human EGF receptor proto‐oncogene. Science 1987; 238: 1408–10. [DOI] [PubMed] [Google Scholar]
  • 9. Yamazaki H, Fukui Y, Ueyama Y, Tamaoki N, Kawamoto T, Taniguchi S, Shibuya M. Amplification of the structurally and functionally altered epidermal growth factor receptor gene (c‐erbB) in human brain tumors. Mol Cell Biol 1988; 8: 1816–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Ekstrand AJ, Sugawa N, James CD, Collins VP. Amplified and rearranged epidermal growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N‐ and/or C‐terminal tails. Proc Natl Acad Sci USA 1992; 89: 4309–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Wong AJ, Ruppert JM, Signer SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA 1992; 89: 2965–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Sugawa N, Ekstrand AJ, James CD, Collins VP. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc Natl Acad Sci USA 1990; 87: 8602–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, Huang HJ. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci USA 1994; 91: 7727–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Ekstrand AJ, Longo N, Hamid ML, Olson JJ, Liu L, Collins VP, James CD. Functional characterization of an EGF receptor with a truncated extracellular domain expressed in glioblastomas with EGFR gene amplification. Oncogene 1994; 9: 2313–20. [PubMed] [Google Scholar]
  • 15. Pedersen MW, Meltorn M, Damstrup L, Poulsen HS. The type III epidermal growth factor receptor mutation. Biological significance and potential target for anti‐cancer therapy. Ann Oncol 2001; 12: 745–60. [DOI] [PubMed] [Google Scholar]
  • 16. Moscatello DK, Montgomery RB, Sundareshan P, McDanel H, Wong MY, Wong AJ. Transformational and altered signal transduction by a naturally occurring mutant EGF receptor. Oncogene 1996; 13: 85–96. [PubMed] [Google Scholar]
  • 17. Moscatello DK, Holgado‐Madruga M, Emlet DR, Montgomery RB, Wong AJ. Constitutive activation of phosphatidylinositol 3‐kinase by a naturally occurring mutant epidermal growth factor receptor. J Biol Chem 1998; 273: 200–6. [DOI] [PubMed] [Google Scholar]
  • 18. Antonyak MA, Moscatello DK, Wong AJ. Constitutive activation of c‐Jun N‐terminal kinase by a mutant epidermal growth factor receptor. J Biol Chem 1998; 273: 2817–22. [DOI] [PubMed] [Google Scholar]
  • 19. Chu CT, Everiss KD, Wikstrand CJ, Batra SK, Kung HJ, Bigner DD. Receptor dimerization is not a factor in the signalling activity of a transforming variant epidermal growth factor receptor (EGFRvIII). Biochem J 1997; 324:855–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Huang HS, Nagane M, Klingbeil CK, Lin H, Nishikawa R, Ji XD, Huang CM, Gill GN, Wiley HS, Cavenee WK. The enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phosphorylation and unattenuated signaling. J Biol Chem. 1997; 272: 2927–35. [DOI] [PubMed] [Google Scholar]
  • 21. de Garcia Palazzo IE, Adams GP, Sundareshan P, Wong AJ, Testa JR, Bigner DD, Weiner LM. Expression of mutated epidermal growth factor receptor by non‐small cell lung carcinomas. Cancer Res 1993; 53: 3217–20. [PubMed] [Google Scholar]
  • 22. Moscatello DK, Holgado‐Madruga M, Godwin AK, Ramirez G, Gunn G, Zoltick PW, Biegel JA, Hayes RL, Wong AJ. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res 1995; 55: 5536–9. [PubMed] [Google Scholar]
  • 23. Wikstrand CJ, Hale LP, Batra SK, Hill ML, Humphrey PA, Kurpad SN, McLendon RE, Moscatello D, Pegram CN, Reist CJ, Traweek ST, Wong AJ, Zalutsky MR, Bigner DD. Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas. Cancer Res 1995; 55: 3140–8. [PubMed] [Google Scholar]
  • 24. Nagane M, Coufal F, Lin H, Bogler O, Cavenee WK, Huang HJ. A common mutant epidermal growth factor receptor confers enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis. Cancer Res 1996; 56: 5079–86. [PubMed] [Google Scholar]
  • 25. Olapade‐Olaopa EO, Moscatello DK, MacKay EH, Horsburgh T, Sandhu DP, Terry TR, Wong AJ, Habib FK. Evidence for the differential expression of a variant EGF receptor protein in human prostate cancer. Br J Cancer 2000; 82: 186–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Tang CK, Gong XQ, Moscatello DK, Wong AJ, Lippman ME. Epidermal growth factor receptor vIII enhances tumorigenicity in human breast cancer. Cancer Res 2000; 60: 3081–7. [PubMed] [Google Scholar]
  • 27. Moscatello DK, Ramirez G, Wong AJ. A naturally occurring mutant human epidermal growth factor receptor as a target for peptide vaccine immunotherapy of tumors. Cancer Res 1997; 57: 1419–24. [PubMed] [Google Scholar]
  • 28. Sampson JH, Crotty LE, Lee S, Archer GE, Ashley DM, Wikstrand CJ, Hale LP, Small C, Dranoff G, Friedman AH, Friedman HS, Bigner DD. Unarmed, tumor‐specific monoclonal antibody effectively treats brain tumors. Proc Natl Acad Sci USA 2000; 97: 7503–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Luwor RB, Johns TG, Murone C, Huang HJ, Cavenee WK, Ritter G, Old LJ, Burgess AW, Scott AM. Monoclonal antibody 806 inhibits the growth of tumor xenografts expressing either the de2–7 or amplified epidermal growth factor receptor (EGFR) but not wild‐type EGFR. Cancer Res 2001; 61: 5355–61. [PubMed] [Google Scholar]
  • 30. Mishima K, Johns TG, Luwor RB, Scott AM, Stockert E, Jungbluth AA, Ji XD, Suvarna P, Voland JR, Old LJ, Huang HS, Cavenee WK. Growth suppression of intracranial xenografted glioblastomas overexpressing mutant epidermal growth factor receptors by systemic administration of monoclonal antibody (mAb) 806, a novel monoclonal antibody directed to the receptor. Cancer Res 2001; 61: 5349–54. [PubMed] [Google Scholar]
  • 31. Bunn PA Jr, Kato H. Current perspectives in the treatment of non‐small cell lung cancer. Semin Oncol 2001; 28: 1–2. [Google Scholar]
  • 32. Auerbach O, Stout AP, Hammond EC, Garfinkel L. Changes in bronchial epithelium in relation to sex, age, residence, smoking and pneumonia. N Engl J Med 1962; 267: 111–9. [DOI] [PubMed] [Google Scholar]
  • 33. Pastorino U, Sozzi G, Miozzo M, Tagliabue E, Pilotti S, Pierotti MA. Genetic changes in lung cancer. J Cell Biochem 1993; 17F Suppl: 237–48. [DOI] [PubMed] [Google Scholar]
  • 34. Reissmann RT, Koga H, Figlin RA, Holmes EC, Slamon DJ. Amplification and Overexpression of the cyclin D1 and epidermal growth factor receptor genes in non‐small‐cell lung cancer. J Cancer Res Clin Oncol 1999; 125: 61–70. [DOI] [PubMed] [Google Scholar]
  • 35. Arteaga CL, Johnson DH. Tyrosine kinase inhibitors–ZD1839 (Iressa). Curr Opin Oncol 2001; 13: 491–8. [DOI] [PubMed] [Google Scholar]

Articles from Cancer Science are provided here courtesy of Wiley

RESOURCES