Suppression of ovarian cancer cell tumorigenicity and evasion of cisplatin resistance using a truncated epidermal growth factor receptor in a rat model

John K. Chan, Huyen Pham, Juan You Xue, Noelle G. Cloven, Robert A. Burger, G. Scott Rose, Kristi Van Nostrand, Murray Korc, Philip J. DiSaia, Hung Fan

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32 Scopus citations

Abstract

The overexpression of the epidermal growth factor receptor (EGFR) is associated with a poor prognosis in ovarian cancer. The dominant-negative EGFR (EGFR-DNR) is a truncated receptor that lacks the tyrosine kinase domain and is devoid of signaling capability. This study tested the effects of a EGFR-DNR approach in ovarian cancer cells. NuTu-19, a rat ovarian cancer cell line was rendered resistant to cisplatin. Both NuTu-19 and resistant cells were infected with a retroviral vector containing the EGFR-DNR. NuTu-19 and NuTu-DNR (NuTu-19 cells expressing the EGFR-DNR) were injected into Fisher 344 immunocompetent rats. Western blot analyses were used to assess signal transduction pathways. All rats injected with NuTu-DNR cells remained healthy following tumor injection. In contrast, 100% of the rats injected with the NuTu-19 and NuTu-Sham (NuTu-19 cells expressing an empty vector) died of disease progression at the end of 15 weeks (P = 0.00009). On Western blot analysis, both NuTu-19 and NuTu-Sham cells showed a strong activation of mitogen-activated protein kinase (MAPK) after exposure to EGF. Cisplatin-resistant cell lines showed an enhanced EGF stimulatory effect via the MAPK pathway compared with parental cells. The EGFR-DNR significantly reduced the ability of EGF to induce cell signaling through the MAPK pathway. Lastly, the EGFR-DNR can partially reverse cisplatin resistance in drug-resistant cells. The EGFR-DNR approach suggests that EGFR confers a growth advantage to NuTu-19 cells in vivo. Thus, EGFR blockade may ultimately prove to be a useful therapeutic tool in the treatment of cisplatin-sensitive and cisplatin-resistant ovarian cancers.

Original languageEnglish (US)
Pages (from-to)3243-3248
Number of pages6
JournalCancer Research
Volume65
Issue number8
DOIs
StatePublished - Apr 15 2005

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Chan, J. K., Pham, H., Xue, J. Y., Cloven, N. G., Burger, R. A., Rose, G. S., Van Nostrand, K., Korc, M., DiSaia, P. J., & Fan, H. (2005). Suppression of ovarian cancer cell tumorigenicity and evasion of cisplatin resistance using a truncated epidermal growth factor receptor in a rat model. Cancer Research, 65(8), 3243-3248. https://doi.org/10.1158/0008-5472.CAN-03-3013