Molecular mechanisms regulating traffic of EGF receptor and their role in modulating responses to cancer therapeutics

点击翻译按钮获取中文摘要

The epidermal growth factor receptor (EGFR) is a protein expressed in normal growing cells and its expression is increased in cancer cells. Following activation of EGFR it is internalized from the cell membrane into the cell interior and can subsequently either be degraded or recycled to the cell surface. EGFR has recently also been reported to enter the nucleus after activation where it can regulate repair of DNA damage and switch on genes which promote cell proliferation. The molecular mechanisms that regulate traffic of EGFR into the nucleus are currently unknown. The development of EGFR inhibitors is a major advance in targeted cancer therapy. However these agents have limited activity when used alone and optimal results occur with combinations including chemotherapy and radiotherapy. There is no clear understanding of the mechanisms whereby EGFR inhibitors modulate effects of chemotherapy and radiation, although there are indications that repair of DNA damage and cell death (apoptosis) pathways are affected. This project aims to investigate the mechanisms of these interactions by examining in detail the mechanisms by which EGFR is transported throughout the cell and into the nucleus. The effects of altered cellular location will be integrated with studies of how this affects radiation and drug damage. This understanding will allow the better prediction of likely responses to cancer therapy, will facilitate the design of optimal combinations in future clinical trials and may identify novel therapeutic targets for the design of novel cancer treatments.