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

表皮生长因子受体（EGFR）在许多实体瘤中过表达，并与治疗耐药性相关。最近的数据表明，EGFR在响应细胞应激暴露的DNA修复过程的调节中起着至关重要的作用。因此，基于EGFR的放射肿瘤学干预策略旨在增加未修复的双链断裂的量，以诱导细胞死亡。正如我们所展示的，细胞核EGFR参与异染色质DNA内双链断裂的修复。核EGFR调节TIP60乙酰转移酶的活性，这是组蛋白H3乙酰化所必需的。H3乙酰化触发染色质结构的开放，以实现DNA修复过程。本研究的目的是了解爱必妥治疗对EGFR依赖性染色质重塑的影响，这也可能阐明爱必妥耐药。src抑制剂达沙替尼或T654适体对细胞核EGFR转运的阻断作用（与DNA修复抑制相关）将在采用xenocraft模型的动物研究中进行研究。应阐明核EGFR对TIP60活性调节的关键作用，并研究对遗传毒性治疗（如顺铂或乳头状瘤病毒E6蛋白）的干扰。最后，EGFR在调节线粒体活性响应辐射的作用的问题将得到解决，以更好地了解细胞应激管理中EGFR的功能。

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.