Combining radiotherapy with DNA repair inhibitors in the lab and the clinic


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Anthony Chalmers1
1University of Glasgow, Glasgow, UK

Abstract

Radiotherapy kills cancer cells by damaging their DNA, so the ability to repair radiation-induced DNA damage is fundamental to treatment resistance. Increasing understanding of the DNA damage response and the availability of specific inhibitors of components of this response is enabling the development of therapeutic strategies with potential to enhance radiation sensitivity in a tumour specific manner. Inhibitors of poly(ADP-ribose polymerase) (PARP) are currently being studied in combination with radiotherapy in phase I studies in a number of tumour sites.

The emergence of the cancer stem cell hypothesis has added another layer to this field of research, with certain tumour stem cells exhibiting radiation resistance through upregulation of the DNA damage response. Targeting S-phase and G2/M checkpoint activation through ATR or Chk1 generates moderate radiation resistance that is mitigated by the enhanced DNA repair capacity of the cancer stem cells. Dual targeting of both cell cycle checkpoints and DNA repair appears to generate optimum radiosensitisation in these populations and is a promising therapeutic strategy.