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  • Original Paper
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EGFRvIII-mediated radioresistance through a strong cytoprotective response

Abstract

The constitutively active, truncated epidermal growth factor receptor EGFRvIII lacks the ability of EGF binding due to a deletion of the NH2-terminal domain. EGFRvIII confers increased tumorigenicity, is coexpressed with EGFR wild type (wt) in human carcinoma and malignant glioma cells when grown as xenografts, but is not expressed in vitro. The effects of EGFRvIII expression on cellular radiation responses were studied in Chinese hamster ovary (CHO) cells transfected with plasmids expressing EGFRvIII (CHO.EGFRvIII) or EGFRwt (CHO.EGFRwt). CHO cells expressing similar levels of either receptor were employed to define their roles in response to EGF and ionizing radiation. EGF activated EGFRwt with no effect on EGFRvIII. In contrast, a single radiation exposure of 2 Gy resulted in a 2.8- and 4.3-fold increase in Tyr phosphorylation of EGFRwt and EGFRvIII, respectively. Downstream consequences of this radiation-induced activation were examined by inhibiting EGFRwt and EGFRvIII with AG1478 (kinase inhibitor). The radiation-induced 8.5-fold activation of the pro-proliferative mitogen-activated protein kinase and the 3.2-fold stimulation of the antiapoptotic AKT/phosphatidylinositol-3-kinase pathways by EGFRvIII far exceeded that in CHO.EGFR wt cells. Thus, based on colony formation and apoptosis assays, EGFRvIII expression conferred a stronger cytoprotective response to radiation than EGFRwt, resulting in relative radioresistance. Therefore, disabling EGFRvIII in addition to EGFRwt needs to be considered in any therapeutic approach aimed at targeting EGFR for tumor cell radiosensitization.

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Acknowledgements

This research was supported by PHS Grants P01 CA72955 and R01CA65896 (to R Schmidt-Ullrich) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; by the Florence and Hyman Meyers Head and Neck Cancer Research Fund; by the Deutsche Krebshilfe, Dr Mildred Scheel Stiftung fellowship support (to G Lammering); and by Grant DAMD17-99-1-9426 (to P Dent) from the US Army. We acknowledge the F-test executed by Kathy Dawson, PhD, VCU, Department of Biostatistics.

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Correspondence to Rupert K Schmidt-Ullrich.

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Lammering, G., Hewit, T., Valerie, K. et al. EGFRvIII-mediated radioresistance through a strong cytoprotective response. Oncogene 22, 5545–5553 (2003). https://doi.org/10.1038/sj.onc.1206788

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