Skip to main content

Advertisement

Log in

Epithelial growth factor receptor (EGFR) pathway and renal cell carcinoma

  • Review
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

The epidermal growth factor receptor (EGFR) pathway is a very well-known pathway implicated in proliferation, growth and metastatic development of various tumor types. Consequently, EGFR pathway inhibitors have provided clinical benefits in many tumor types. EGFR expression is reported in up to 95% of renal cell carcinoma (RCC) and is considered high (3+) in up to 60%. In preclinical models, the EGFR pathway appears implicated in tumor development. Its mode of action includes the common EGFR signal transduction cascades, but it also interacts with the angiogenic pathway, especially the vascular endothelial growth factor receptor (VEGFR) pathway. Monotherapy with EGFR pathway inhibitors does not appear to modify the history of metastatic RCC (MRCC) and does not justify further experiments in this setting. The issues now requiring attention are the degree to which the EGFR pathway is involved in RCC tumors expressing high EGFR levels—a phase III study suggests that it influences outcome in these patients—and the clinical benefit of associating antiangiogenic therapy and EGFR pathway inhibitors in the light of successive phases II trials. In conclusion, the EGFR pathway is probably not a major pathway in RCC development compared to the antiangiogenic pathways, but could play a role in association with antiangiogenics or in the event of progression after antiangiogenic therapy. Additional preclinical data is needed to support these hypotheses.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Ravaud A, Debled M (1999) Present achievements in the medical treatment of metastatic renal cell carcinoma. Crit Rev Oncol Hematol 31:77–87

    PubMed  CAS  Google Scholar 

  2. Fyfe G, Fisher RI, Rosenberg SA et al (1995) Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 13:688–696

    PubMed  CAS  Google Scholar 

  3. Negrier S, Escudier B, Lasset C et al (1998) Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal cell carcinoma. N Engl J Med 338:1272–1278

    Article  PubMed  CAS  Google Scholar 

  4. Medical Research Council Renal Cancer Collaborators (1999) Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial.Lancet 353:14–17

    Article  Google Scholar 

  5. Bui MH, Seligson D, Han KR et al (2003) Carbonic anhydrase IX as an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res 9:802–811

    PubMed  CAS  Google Scholar 

  6. Negrier S, Perol D, Ravaud A et al (2006) Is intravenous IL2 superior to subcutaneous IL2 in good prognosis patients with metastatic renal cell carcinoma receiving a combination of IL2 and alpha interferon? Results of the prospective randomized PERCY Duo trial. Proc Am Soc Clin Oncol 24:225s, (Abstract 4536)

    Google Scholar 

  7. Negrier S, Perol D, Ravaud A et al (2005) Do cytokines improve survival in patients with metastatic renal cell carcinoma of intermediate prognosis? Results of the prospective randomized PERCY Quattro trial. Proc Am Soc Clin Oncol 23:380s, (Abstract 4511)

    Google Scholar 

  8. Yang JC, Haworth L, Sherry RM et al (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–4349

    Article  PubMed  CAS  Google Scholar 

  9. Escudier B, Szczylik C, Eisen T et al (2005) Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY-439006) in patients with advanced renal cell carcinoma. Proc Am Soc Clin Oncol 23:380s, (Abstract 4510)

    Google Scholar 

  10. Motzer RJ, Hutson TE, Tomczk P et al (2006) Phase III randomized trial of sunitinib malate (SU 11248) as first-line systemic therapy for patients with metastatic renal cell carcinoma. Proc Am Soc Clin Oncol 24:2s, (Abstract 3)

    Google Scholar 

  11. Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225

    Article  PubMed  CAS  Google Scholar 

  12. Slichenmyer WJ, Fry DW (2001) Anticancer therapy targeting ErbB family of receptor tyrosine kinases. Semin Oncol 28 (Suppl 16):67–79

    Article  PubMed  CAS  Google Scholar 

  13. Herbst RS, Shin DM (2002) Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy. Cancer 94:1593–1611

    Article  PubMed  CAS  Google Scholar 

  14. Olayioye M, Neve R, Lane H, et al (2000) The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 19:3159–3167

    Article  PubMed  CAS  Google Scholar 

  15. Alroy I, Yarden Y (1997) The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. FEBS Lett 410: 83–86

    Article  PubMed  CAS  Google Scholar 

  16. Lewis TS, Shapiro PS, Ahn NG (1998) Signal transduction through MAP kinase cascades. Adv Cancer Res 74:49–139

    Article  PubMed  CAS  Google Scholar 

  17. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase-Akt pathway in human cancer. Nat Rev Cancer 2:489–501

    Article  PubMed  CAS  Google Scholar 

  18. Okamura K, Morimoto A, Hamanaka R et al (1992) A model system of tumour angiogenesis: involvement of transforming growth factor-a in tube formation of human microvascular endothelial cells induced by oesophageal cancer. Biochem Biophys Res Commun 186:1471–1479

    Article  PubMed  CAS  Google Scholar 

  19. Hirata A, Ogawa S, Kometani T et al (2002) ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res 62:2554–2560

    PubMed  CAS  Google Scholar 

  20. Baker CH, Solorzano CC, Fidler IJ (2002) Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer. Cancer Res 62:1996–2003

    PubMed  CAS  Google Scholar 

  21. Goldman CK, Kim J, Wong WL et al (1993) Epidermal growth factor stimulates vascular endothelial growth factor production by human glioma cells: a model of glioblastoma multiforme pathophysiology. Mol Biol Cell 4:121–133

    PubMed  CAS  Google Scholar 

  22. Akagi M, Kawaguchi M, Liu W et al (2003) Induction of neuropilin-1 and vascular endothelial growth factor by epidermal growth factor in human gastric cancer cells. Br J Cancer 88:796–802

    Article  PubMed  CAS  Google Scholar 

  23. Perrotte P, Matsumoto T, Inoue K et al (1999) Anti-epidermal growth factor receptor anti-body C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 5:257–265

    PubMed  CAS  Google Scholar 

  24. Kumar R, Yarmand-Bagheri R (2001) The role of HER2 in angiogenesis. Semin Oncol 28:27–32

    Article  PubMed  CAS  Google Scholar 

  25. Bruns CJ, Solorzano CC, Harbison MT et al (2000) Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res 60:2926–2935

    PubMed  CAS  Google Scholar 

  26. Oh HY, Kwon SM, Kim SI et al (2005) Antiangiogenic effect of ZD 1839 against murine renal cell carcinoma (RENCA) in an orthotopic mouse model. Urol Int 75:159–165

    Article  PubMed  CAS  Google Scholar 

  27. Kedar D, Baker CH, Killion JJ et al (2002) Blockade of the epidermal growth factor receptor signaling inhibits angiogenesis leading to regression of human renal cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 8:592–600

    Google Scholar 

  28. Gomella LG, Anglard P, Sargent ER et al (1990) Epidermal growth factor receptor gene analysis in renal cell carcinoma. J Urol 143:191–193

    PubMed  CAS  Google Scholar 

  29. Ishikawa J, Maeda S, Umezu K et al (1990) Amplification and overexpression of the epidermal growth factor receptor gene in human renal-cell carcinoma. Int J Cancer 45:1018–1021

    Article  PubMed  CAS  Google Scholar 

  30. Moch H, Sauter G, Buchholz N et al (1997) Epidermal growth factor receptor expression is associated with rapid tumor cell proliferation in renal cell carcinoma. Human Pathol 28:1255–1259

    Article  CAS  Google Scholar 

  31. Hofmockel G, Riess S, Bassukas ID et al (1997) Epidermal growth factor family and renal cell carcinoma: expression and prognostic impact. Eur Urol 31:478–484

    PubMed  CAS  Google Scholar 

  32. Ravaud A, Gardner J, Hawkins R et al (2006) Efficacy of lapatinib in patients with high tumor EGFR expression: results of a phase III trial in advanced renal cell carcinoma. Proc Am Soc Clin Oncol 24:217s, (Abstract 4502)

    Google Scholar 

  33. Langner C, Ratschek M, Rehak P et al (2004) Are heterogeneous results of EGFR immunoreactivity in renal cell carcinoma related to non-standardised criteria for staining evaluation? J Clin Pathol 57:773–775

    Article  PubMed  CAS  Google Scholar 

  34. Merseburger AS, Hennenlotter J, Simon P et al (2005) Membranous expression and prognostic implications of epidermal growth factor receptor protein in human renal cell cancer. Anticancer Res 25:1901–1907

    PubMed  CAS  Google Scholar 

  35. Seliger B, Rongcun Y, Atkins D et al (2000) Her-2/neu is expressed in human renal cell carcinoma at heterogeneous levels independently of tumor grading and staging and can be recognized by HLA-A2.1-restricted cytotoxic T lymphocytes. Int J Cancer 87:349–359

    Article  PubMed  CAS  Google Scholar 

  36. Stumm G, Eberwein S, Rostock-Wolf S et al (1996) Concomitant overexpression of the EGFR and erbB-2 genes in renal cell carcinoma (RCC) is correlated with differentiation and metastasis. Int J Cancer 69:17–22

    Article  PubMed  CAS  Google Scholar 

  37. Paez JG, Janne PA, Lee JC et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500

    Article  PubMed  CAS  Google Scholar 

  38. Lynch TJ, Bell DW, Sordella R et al (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–20132

    Article  PubMed  CAS  Google Scholar 

  39. Sakaeda T, Okumura N, Gotoh A et al (2005) EGFR mRNA is upregulated, but somatic mutations of the gene are hardly found in renal cell carcinoma in Japanese patients. Pharm Res 22:1757–1761

    Article  PubMed  CAS  Google Scholar 

  40. Hawkins RE, Ravaud A, von der Maase H et al (2006) Lapatinib extend survival in patients with high ErbB1 tumor expression: subgroup results of a phase III trial in advanced renal cell carcinoma. Ann Oncol 17 (Suppl 9):ix 145, (Abstract 4400)

    Google Scholar 

  41. Everitt JI, Walker CL, Goldsworthy TW et al (1997) Altered expression of transforming growth factor-alpha: an early event in renal cell carcinoma development. Mol Carcinogen 19:213–219

    Article  CAS  Google Scholar 

  42. Price JT, Wilson HM, Haites NE (1996) Epidermal growth factor increases the in vitro invasion, motility and adhesion interactions of the primary renal carcinoma cell line, A 704. Eur J Cancer 32 A:1977–1982

    Article  Google Scholar 

  43. Asakuma J, Sumimoto M, Asano T et al (2004) Modulation of tumor growth and tumor induced angiogenesis after epidermal growth factor receptor inhibition by ZD 1839 in renal cell carcinoma. 171:897–902

    Google Scholar 

  44. Prewett M, Rothman M, Waksal H et al (1998) Mouse-human chimeric anti-epidermal growth factor receptor antibody C225 inhibits the growth of human renal cell carcinoma xenografts in nude mice. Clin Cancer Res 4:2957–2966

    PubMed  CAS  Google Scholar 

  45. De Paulsen N, Brychzy A, Fournier MC et al (2001) Role of transforming growth factor-alpha in von Hippel-Lindau (VHL)(−/−) clear cell renal carcinoma cell proliferation: a possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis. Proc Natl Acad Sci USA 98:1387–1392

    Article  PubMed  Google Scholar 

  46. Gunaratnam L, Morley M, Franovic A et al (2003) Hypoxia inducible factor activates the transforming growth factor-alpha/epidermal growth factor receptor growth stimulatory pathway in VHL (−/−) renal cell carcinoma cells. J Biol Chem 278:44966–44974

    Article  PubMed  CAS  Google Scholar 

  47. Smith K, Gunaratnam, Morley M et al (2005) Silencing of epidermal growth factor receptor suppresses hypoxia-inducible factor-2-driven VHL −/− renal cancer. Cancer Res 65:5221–5230

    Article  PubMed  CAS  Google Scholar 

  48. Perera AD, Kleymenova EV, Walker CL et al (2000) Requirement for the von Hippel-Lindau tumor suppressor gene for functional epidermal growth factor receptor blockade by monoclonal antibody C225 in renal cell carcinoma. Clin Cancer Res 6:1518–1523

    PubMed  CAS  Google Scholar 

  49. Lager DJ, Slagel DD, Palechek PL (1994) The expression of epidermal growth factor receptor and transforming growth factor alpha in renal cell carcinoma. Modern Pathol 7:544–548

    CAS  Google Scholar 

  50. Ljungberg B, Grafvels M, Damber JE (1994) Epidermal growth factor receptor gene expression and binding capacity in renal cell carcinoma, in relation to tumor stage, grade and DNA ploidy. Uroligical Res 22:305–308

    Article  CAS  Google Scholar 

  51. Kallio JP, Hirvikoski P, Helin H et al (2003) Membranous location of EGFR immunostaining is associated with good prognosis in renal cell carcinoma. Br J Cancer 89:1266–1269

    Article  PubMed  CAS  Google Scholar 

  52. Prewett M, Rothman M, Waksal H et al (1998) Mouse-human chimeric anti-epidermal growth factor receptor antibody C225 inhibits the growth of human renal cell carcinoma xenografts in nude mice. Clin Cancer Res 4:2957–2966

    PubMed  CAS  Google Scholar 

  53. Motzer RJ, Amato R, Todd M et al (2003) Phase II trial of antiepidermal growth factor receptor antibody C225 in patients with advanced renal cell carcinoma. Invest New Drugs 21:99–101

    Article  PubMed  CAS  Google Scholar 

  54. Yang X-D, Jia X-C, Corvalan JRF et al (1999) Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res 59:1236–1243

    PubMed  CAS  Google Scholar 

  55. Yang XD, Jia XC, Corvalan JRF et al (2001) Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody for cancer therapy. Crit Rev Oncol Hematol 38:17–23

    PubMed  CAS  Google Scholar 

  56. Rowinsky EK, Schwartz GH, Gollob JA et al (2004) Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer. J Clin Oncol 22:3003–3015

    Article  PubMed  CAS  Google Scholar 

  57. Drucker B, Bacik J, Ginsberg M et al (2003) Phase II trial of ZD 1839 (Iressa) in patients with advanced renal cell carcinoma. Invest New Drugs 21:341–345

    Article  PubMed  CAS  Google Scholar 

  58. Dawson NA, Guo C, Zak R et al (2004) A phase II trial of gefitinib (Iressa, ZD 1839) in stage IV and recurrent renal cell carcinoma. Clin Cancer Res 10:7812–7819

    Article  PubMed  CAS  Google Scholar 

  59. Jermann M, Stahel RA, Salzberg M et al (2006) A phase II, open-label study of gefitinib (Iressa) in patients with locally advanced, metastatic, or relapsed renal-cell carcinoma. Cancer Chemother Pharmacol 57:533–539

    Article  PubMed  CAS  Google Scholar 

  60. Hidalgo M, Siu LL, Nemunaitis J et al (2001) Phase I and pharmacology study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267–3279

    PubMed  CAS  Google Scholar 

  61. Mekhail TM, Abou-Jawde RM, Boumerhi G et al (2005) Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol 23:832–841

    Article  PubMed  Google Scholar 

  62. Motzer RJ, Mazumdar M, Bacik J et al (1999) Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 17:2530–2540

    PubMed  CAS  Google Scholar 

  63. Hainsworth JD, Sosman JA, Spigel DR et al (2005) Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 23:7889–7896

    Article  PubMed  CAS  Google Scholar 

  64. Bukowski RM, Kabbinavar F, Figlin RA et al (2006) Bevacizumab with or without erlotinib in metastatic renal cell carcinoma. Proc Am Soc Clin Oncol 24:18S, (Abstract 4523)

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alain Ravaud.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ravaud, A., de Clermont, H., Pasticier, G. et al. Epithelial growth factor receptor (EGFR) pathway and renal cell carcinoma. Targ Oncol 2, 99–105 (2007). https://doi.org/10.1007/s11523-007-0044-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-007-0044-7

Keywords

Navigation