Inhibiting the DNA damage response as a therapeutic manoeuvre in cancer

The DNA damage response (DDR), consisting of an orchestrated network of proteins effecting repair and signalling to cell cycle arrest, to allow time to repair, is essential for cell viability and to prevent DNA damage being passed on to daughter cells. The DDR is dysregulated in cancer with some pathways up-regulated and others down-regulated or lost. Up-regulated pathways can confer resistance to anti-cancer DNA damaging agents. Therefore, inhibitors of key components of these pathways have the potential to prevent this therapeutic resistance. Conversely, defects in a particular DDR pathway may lead to dependence on a complementary pathway. Inhibition of this complementary pathway may result in tumour-specific cell killing. Thus, inhibitors of the DDR have the potential to increase the efficacy of DNA damaging chemotherapy and radiotherapy and have single-agent activity against tumours with a specific DDR defect. This review describes the compounds that have been designed to inhibit specific DDR targets and summarizes the pre-clinical and clinical evaluation of these inhibitors of DNA damage signalling and repair.