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S014 PARP inhibitors for cancer therapy Nicola Curtin Newcastle University, Newcastle upon Tyne, UK Poly(ADP-ribose) polymerase (PARP)is a DNA damage-activated enzyme that catalyses the formation of ADP ribose polymers from NAD+. It plays a key role in the repair of DNA breaks and PARP inhibitors (PARPi) were first developed with the purpose of increasing the persistence of DNA damage in order to increase the antitumour activity of DNA damaging anticancer agents. Over the last 3 decades PARPi of increasing potency have been developed, virtually all contain the nicotinamide pharmacophore. PARPi increase the persistence of DNA single and double strand breaks and enhance the cytotoxicity and antitumour activity of DNA methylating agents, topoisomerase I poisons and ionising radiation. However, it was the discovery that PARPi selectively killed cells and tumour xenografts defective in homologous recombination repair (HRR) that led to a heightened interest in PARPi. This phenomenon of “synthetic lethality”, where inactivation of one of 2 complementary pathways alone does not affect viability but inactivation of both together is lethal, is a new paradigm in cancer therapy. HRR defects are relatively common in tumours, the classic example being mutations in the breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2. The first cancer patient was treated with a PARPi in 2003 and there are now 9 PARPi undergoing clinical evaluation as single agent or in combination studies.