Implications of EGFR inhibition in ovarian cancer cell proliferation

Shawna L. Bull Phelps, John O. Schorge, Michael J. Peyton, Hisayuki Shigematsu, Li Lin Xiang, David S. Miller, Jayanthi S. Lea

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Objectives: Epidermal Growth Factor Receptor (EGFR) is one of the four members of the Human Epidermal Receptor (HER) family and is over-expressed in multiple malignancies. EGFR over-expression in ovarian cancer has been associated with poor prognosis. Targeted inhibition of EGFR via its tyrosine kinase domain is a successful treatment in lung cancer. Our objective was to correlate EGFR over-expression and growth inhibition, by EGF receptor inhibitors, in ovarian cancer. Materials and methods: HER expression in nine epithelial ovarian cancer cell lines and one lung cancer cell line was determined by Western blot analysis. EGFR phosphorylation sites were analyzed and DNA sequencing was performed. Cell proliferation assays were performed in the presence of the tyrosine kinase inhibitor, gefitinib, and the EGFR monoclonal antibody, cetuximab. Inhibitory concentrations of 50% of these therapies were determined and compared across all cell lines. The lung cancer cell line, HCC827, was used as a control. Results: Four of nine (44%) ovarian cancer cell lines and the control lung cancer cell line expressed EGFR. These same cell lines showed a common phosphorylated residue at position 992, while other residues were variably phosphorylated. All but one cell line expressed at least one HER family member. Mutational analysis of the ovarian cancer cell lines showed no mutations in EGFR exons 18-21. Cell proliferation assays using gefitinib and cetuximab showed minimal response in the ovarian cancer cell lines when compared to the control HCC827, but relative sensitivity compared to the one cell line that had no HER family expression. Conclusions: Ovarian cancer cell lines show variable expression of activated EGFR. EGFR inhibition alone, in ovarian tumors that lack a tyrosine kinase mutation or over-express EGFR is unlikely to result in clinical response.

Original languageEnglish (US)
Pages (from-to)411-417
Number of pages7
JournalGynecologic Oncology
Volume109
Issue number3
DOIs
StatePublished - Jun 2008

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Epidermal Growth Factor Receptor
Ovarian Neoplasms
Cell Proliferation
Cell Line
Lung Neoplasms
Protein-Tyrosine Kinases
Inhibition (Psychology)
Mutation
DNA Sequence Analysis
Inhibitory Concentration 50
Exons
Neoplasms
Western Blotting
Monoclonal Antibodies
Phosphorylation

Keywords

  • EGFR
  • Gefitinib
  • HER
  • Monoclonal antibody
  • Ovarian cancer
  • Tyrosine kinase

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Oncology

Cite this

Bull Phelps, S. L., Schorge, J. O., Peyton, M. J., Shigematsu, H., Xiang, L. L., Miller, D. S., & Lea, J. S. (2008). Implications of EGFR inhibition in ovarian cancer cell proliferation. Gynecologic Oncology, 109(3), 411-417. https://doi.org/10.1016/j.ygyno.2008.02.030

Implications of EGFR inhibition in ovarian cancer cell proliferation. / Bull Phelps, Shawna L.; Schorge, John O.; Peyton, Michael J.; Shigematsu, Hisayuki; Xiang, Li Lin; Miller, David S.; Lea, Jayanthi S.

In: Gynecologic Oncology, Vol. 109, No. 3, 06.2008, p. 411-417.

Research output: Contribution to journalArticle

Bull Phelps, SL, Schorge, JO, Peyton, MJ, Shigematsu, H, Xiang, LL, Miller, DS & Lea, JS 2008, 'Implications of EGFR inhibition in ovarian cancer cell proliferation', Gynecologic Oncology, vol. 109, no. 3, pp. 411-417. https://doi.org/10.1016/j.ygyno.2008.02.030
Bull Phelps SL, Schorge JO, Peyton MJ, Shigematsu H, Xiang LL, Miller DS et al. Implications of EGFR inhibition in ovarian cancer cell proliferation. Gynecologic Oncology. 2008 Jun;109(3):411-417. https://doi.org/10.1016/j.ygyno.2008.02.030
Bull Phelps, Shawna L. ; Schorge, John O. ; Peyton, Michael J. ; Shigematsu, Hisayuki ; Xiang, Li Lin ; Miller, David S. ; Lea, Jayanthi S. / Implications of EGFR inhibition in ovarian cancer cell proliferation. In: Gynecologic Oncology. 2008 ; Vol. 109, No. 3. pp. 411-417.
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abstract = "Objectives: Epidermal Growth Factor Receptor (EGFR) is one of the four members of the Human Epidermal Receptor (HER) family and is over-expressed in multiple malignancies. EGFR over-expression in ovarian cancer has been associated with poor prognosis. Targeted inhibition of EGFR via its tyrosine kinase domain is a successful treatment in lung cancer. Our objective was to correlate EGFR over-expression and growth inhibition, by EGF receptor inhibitors, in ovarian cancer. Materials and methods: HER expression in nine epithelial ovarian cancer cell lines and one lung cancer cell line was determined by Western blot analysis. EGFR phosphorylation sites were analyzed and DNA sequencing was performed. Cell proliferation assays were performed in the presence of the tyrosine kinase inhibitor, gefitinib, and the EGFR monoclonal antibody, cetuximab. Inhibitory concentrations of 50{\%} of these therapies were determined and compared across all cell lines. The lung cancer cell line, HCC827, was used as a control. Results: Four of nine (44{\%}) ovarian cancer cell lines and the control lung cancer cell line expressed EGFR. These same cell lines showed a common phosphorylated residue at position 992, while other residues were variably phosphorylated. All but one cell line expressed at least one HER family member. Mutational analysis of the ovarian cancer cell lines showed no mutations in EGFR exons 18-21. Cell proliferation assays using gefitinib and cetuximab showed minimal response in the ovarian cancer cell lines when compared to the control HCC827, but relative sensitivity compared to the one cell line that had no HER family expression. Conclusions: Ovarian cancer cell lines show variable expression of activated EGFR. EGFR inhibition alone, in ovarian tumors that lack a tyrosine kinase mutation or over-express EGFR is unlikely to result in clinical response.",
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AU - Bull Phelps, Shawna L.

AU - Schorge, John O.

AU - Peyton, Michael J.

AU - Shigematsu, Hisayuki

AU - Xiang, Li Lin

AU - Miller, David S.

AU - Lea, Jayanthi S.

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N2 - Objectives: Epidermal Growth Factor Receptor (EGFR) is one of the four members of the Human Epidermal Receptor (HER) family and is over-expressed in multiple malignancies. EGFR over-expression in ovarian cancer has been associated with poor prognosis. Targeted inhibition of EGFR via its tyrosine kinase domain is a successful treatment in lung cancer. Our objective was to correlate EGFR over-expression and growth inhibition, by EGF receptor inhibitors, in ovarian cancer. Materials and methods: HER expression in nine epithelial ovarian cancer cell lines and one lung cancer cell line was determined by Western blot analysis. EGFR phosphorylation sites were analyzed and DNA sequencing was performed. Cell proliferation assays were performed in the presence of the tyrosine kinase inhibitor, gefitinib, and the EGFR monoclonal antibody, cetuximab. Inhibitory concentrations of 50% of these therapies were determined and compared across all cell lines. The lung cancer cell line, HCC827, was used as a control. Results: Four of nine (44%) ovarian cancer cell lines and the control lung cancer cell line expressed EGFR. These same cell lines showed a common phosphorylated residue at position 992, while other residues were variably phosphorylated. All but one cell line expressed at least one HER family member. Mutational analysis of the ovarian cancer cell lines showed no mutations in EGFR exons 18-21. Cell proliferation assays using gefitinib and cetuximab showed minimal response in the ovarian cancer cell lines when compared to the control HCC827, but relative sensitivity compared to the one cell line that had no HER family expression. Conclusions: Ovarian cancer cell lines show variable expression of activated EGFR. EGFR inhibition alone, in ovarian tumors that lack a tyrosine kinase mutation or over-express EGFR is unlikely to result in clinical response.

AB - Objectives: Epidermal Growth Factor Receptor (EGFR) is one of the four members of the Human Epidermal Receptor (HER) family and is over-expressed in multiple malignancies. EGFR over-expression in ovarian cancer has been associated with poor prognosis. Targeted inhibition of EGFR via its tyrosine kinase domain is a successful treatment in lung cancer. Our objective was to correlate EGFR over-expression and growth inhibition, by EGF receptor inhibitors, in ovarian cancer. Materials and methods: HER expression in nine epithelial ovarian cancer cell lines and one lung cancer cell line was determined by Western blot analysis. EGFR phosphorylation sites were analyzed and DNA sequencing was performed. Cell proliferation assays were performed in the presence of the tyrosine kinase inhibitor, gefitinib, and the EGFR monoclonal antibody, cetuximab. Inhibitory concentrations of 50% of these therapies were determined and compared across all cell lines. The lung cancer cell line, HCC827, was used as a control. Results: Four of nine (44%) ovarian cancer cell lines and the control lung cancer cell line expressed EGFR. These same cell lines showed a common phosphorylated residue at position 992, while other residues were variably phosphorylated. All but one cell line expressed at least one HER family member. Mutational analysis of the ovarian cancer cell lines showed no mutations in EGFR exons 18-21. Cell proliferation assays using gefitinib and cetuximab showed minimal response in the ovarian cancer cell lines when compared to the control HCC827, but relative sensitivity compared to the one cell line that had no HER family expression. Conclusions: Ovarian cancer cell lines show variable expression of activated EGFR. EGFR inhibition alone, in ovarian tumors that lack a tyrosine kinase mutation or over-express EGFR is unlikely to result in clinical response.

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KW - Ovarian cancer

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