Genetic screens exploring tumour radiosensitivity 


Year:

Session type:

Geoff Higgins1
1Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Oxford, UK

Abstract

Although some key DNA damage repair proteins and signal transduction pathways such as PARP and EGFR are recognised as playing an important role in tumour radiosensitivity, the detailed molecular processes that determine intrinsic radiosensitivity remain largely unclear.

In order to identify novel proteins that regulate tumour radiosensitivity and may hence represent new, clinically useful drug targets, we have undertaken large scale radiosensitivity screens using a druggable genome library of siRNAs targeted against approximately 8000 genes.

This work has identified genes that would not necessarily be expected to play a role in intrinsic radiosensitivity, such as genes involved in vitamin B metabolism.

In addition we have identified genes such as POLQ (DNA polymerase theta), which is overexpressed in multiple different tumour types, and is associated with poor clinical outcomes. Importantly, POLQ is not present in most normal tissues. POLQ knockdown induces tumour cell radiosensitisation without affecting normal tissue cells. If compounds can be developed to successfully inhibit these targets, they may be used clinically to increase the efficacy of radiotherapy without exacerbating normal tissue reactions.