Functional Role of Nuclear Epidermal Growth Receptor (nEGFR) in Response to Irradiation

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The epidermal growth factor receptor (EGFR) is overexpressed in many solid tumors and is associated with treatment resistance. Recent data suggest, that the EGFR plays a crucial role during regulation of DNA-repair processes in response to cellular stress exposure. Consequently, radio-oncological EGFR based intervention strategies intent to increase the amount of unrepaired double strand breaks, to induce cell death. As we could show, nuclear EGFR is involved in repair of double strand breaks within heterochromatic DNA. Nuclear EGFR regulates activity of TIP60 acetyltransferase, which is needed for acetylation of histone H3. H3 acetylation triggers opening of chromatin structure to enable DNA-repair processes. Aim of our study is to understand the effect of Erbitux treatment on EGFR dependent chromatin remodeling in response to irradiation, which may also elucidate Erbitux resistance. Blockage of nuclear EGFR transport by src-inhibitor Dasatinib or T654 aptamer, which are associated with inhibition of DNA-repair, will be investigated in animal studies with xenocraft models. The crucial role of TIP60 activity regulation by nuclear EGFR should be elucidated and the interference with genotoxic treatments, e.g. cisplatin or the E6 protein of papilloma viruses will be investigated. Finally, the question of the role of EGFR during regulation of mitochondrial activity in response to irradiation will be addressed, to better understand the function of EGFR within cellular stress management.