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Epidermal growth factor receptor as a genetic therapy target for carcinoma cell radiosensitization
G Lammering1, T H Hewit, W T Hawkins
1Department of Radiation Oncology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.
Background:
Exposure of human cancer cells to ionizing radiation activates the epidermal growth factor receptor (EGFR), which, in turn, mediates a cytoprotective response that reduces the cells' sensitivity to ionizing radiation. Overexpression of a dominant-negative EGFR mutant, EGFR-CD533, disrupts the cytoprotective response by preventing radiation-induced activation of the receptor and its downstream effectors. To investigate whether gene therapy with EGFR-CD533 has the potential to increase tumor cell radiosensitivity, we introduced an adenoviral vector containing EGFR-CD533 into xenograft tumors in nude mice and evaluated the tumor response to ionizing radiation.
Methods:
Xenograft tumors established from the human mammary carcinoma cell line MDA-MB-231 were transduced via infusion with the adenoviral vector Ad-EGFR-CD533 or a control vector containing the beta-galactosidase gene, Ad-LacZ. The transduced tumors were then exposed to radiation in the therapeutic dose range, and radiation-induced EGFR activation was assessed by examining the tyrosine phosphorylation of immunoprecipitated EGFR. Radiosensitization was determined in vitro by colony-formation assays. All statistical tests were two-sided.
Results:
The transduction efficiency of MDA-MB-231 tumors by Ad-LacZ was 44%. Expression of EGFR-CD533 in tumors reduced radiation-induced EGFR activation by 2.94-fold (95% confidence interval [CI] = 2.23 to 4.14). The radiosensitivity of Ad-EGFR-CD533-transduced tumors was statistically significantly higher (46%; P<.001) than that of Ad-LacZ-transduced tumors, yielding a dose-enhancement ratio of 1.85 (95% CI = 1.54 to 2.51).
Conclusions:
Transduction of MDA-MB-231 xenograft tumors with Ad-EGFR-CD533 conferred a dominant-negative EGFR phenotype and induced tumor radiosensitization. Therefore, disruption of EGFR function through overexpression of EGFR-CD533 may hold promise as a gene therapeutic approach to enhance the sensitivity of tumor cells to ionizing radiation.
Insights
Gene therapy using EGFR-CD533 in tumors significantly increased radiosensitivity by inhibiting epidermal growth factor receptor (EGFR) activation. This approach shows promise for enhancing cancer treatment efficacy with ionizing radiation.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Ionizing radiation activates epidermal growth factor receptor (EGFR) in cancer cells, promoting survival and reducing radiosensitivity.
- A dominant-negative EGFR mutant (EGFR-CD533) can disrupt this protective response by blocking EGFR activation.
Purpose of the Study:
- To investigate the potential of gene therapy using EGFR-CD533 to enhance tumor radiosensitivity.
- To evaluate the effect of Ad-EGFR-CD533 gene transfer on tumor response to ionizing radiation in vivo.
Main Methods:
- Human mammary carcinoma MDA-MB-231 xenograft tumors in nude mice were transduced with Ad-EGFR-CD533 or a control Ad-LacZ vector.
- Tumors were exposed to therapeutic doses of ionizing radiation.
- EGFR activation, radiosensitization, and tumor response were assessed.
Main Results:
- Ad-EGFR-CD533 transduction reduced radiation-induced EGFR activation by 2.94-fold.
- Transduced tumors exhibited significantly higher radiosensitivity (46% increase; P<.001).
- A dose-enhancement ratio of 1.85 was observed, indicating increased efficacy of radiation therapy.
Conclusions:
- Overexpression of EGFR-CD533 via adenoviral vector confers a dominant-negative EGFR phenotype.
- This approach successfully induced tumor radiosensitization in xenograft models.
- Disrupting EGFR function with EGFR-CD533 holds promise as a gene therapy to improve cancer treatment outcomes.