Anti-epidermal growth factor receptor monoclonal antibody cetuximab inhibits EGFR/HER-2 heterodimerization and activation

  • Authors:
    • Dipa Patel
    • Rajiv Bassi
    • Andrea Hooper
    • Marie Prewett
    • Daniel J. Hicklin
    • Xiaoqiang Kang
  • View Affiliations

  • Published online on: January 1, 2009     https://doi.org/10.3892/ijo_00000125
  • Pages: 25-32
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Abstract

Human carcinomas frequently express one or more members of the epidermal growth factor receptor family. Two family members, epidermal growth factor receptor (EGFR) and c-erbB2/neu (HER2), homodimerize or heterodimerize upon activation with ligand and trigger potent mechanisms of cellular proliferation, differentiation and migration. In this study, we examined the effect of the anti-EGFR monoclonal antibody Erbitux™ (cetuximab) on human tumor cells expressing both EGFR and HER2. Investigation of the effect of cetuximab on the activation of EGFR-EGFR, EGFR-HER2 and HER2-HER2 homodimers and heterodimers was conducted using the NCI-N87 human gastric carcinoma cell line. Treatment of NCI-N87 cells with cetuximab completely inhibited formation of EGFR-EGFR homodimers and EGFR-HER2 heterodimers. Activation of HER2-HER2 homodimers was not appreciably stimulated by exogenous ligand and was not inhibited by cetuximab treatment. Furthermore, cetuximab inhibited EGF-induced EGFR and HER2 phosphorylation in CAL27, NCI-H226 and NCI-N87 cells. The activation of downstream signaling molecules such as AKT, MAPK and STAT-3 were also inhibited by cetuximab in these cells. To examine the effect of cetuximab on the growth of tumors in vivo, athymic mice bearing established NCI-N87 or CAL27 xenografts were treated with cetuximab (1 mg, i.p., q3d). The growth of NCI-N87 and CAL27 tumors was significantly inhibited with cetuximab therapy compared to the control groups (p<0.0001 in both cases). In the CAL27 xenograft model, tumor growth inhibition by cetuximab treatment was similar to that by cetuximab and trastuzumab combination treatment. Immunohistological analysis of cetuximab-treated tumors showed a decrease in EGFR-HER2 signaling and reduced tumor cell proliferation. These results suggest that cetuximab may be useful in the treatment of carcinomas co-expressing EGFR and HER2.

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January 2009
Volume 34 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Patel D, Bassi R, Hooper A, Prewett M, Hicklin DJ and Kang X: Anti-epidermal growth factor receptor monoclonal antibody cetuximab inhibits EGFR/HER-2 heterodimerization and activation. Int J Oncol 34: 25-32, 2009.
APA
Patel, D., Bassi, R., Hooper, A., Prewett, M., Hicklin, D.J., & Kang, X. (2009). Anti-epidermal growth factor receptor monoclonal antibody cetuximab inhibits EGFR/HER-2 heterodimerization and activation. International Journal of Oncology, 34, 25-32. https://doi.org/10.3892/ijo_00000125
MLA
Patel, D., Bassi, R., Hooper, A., Prewett, M., Hicklin, D. J., Kang, X."Anti-epidermal growth factor receptor monoclonal antibody cetuximab inhibits EGFR/HER-2 heterodimerization and activation". International Journal of Oncology 34.1 (2009): 25-32.
Chicago
Patel, D., Bassi, R., Hooper, A., Prewett, M., Hicklin, D. J., Kang, X."Anti-epidermal growth factor receptor monoclonal antibody cetuximab inhibits EGFR/HER-2 heterodimerization and activation". International Journal of Oncology 34, no. 1 (2009): 25-32. https://doi.org/10.3892/ijo_00000125