As DNA is frequently subject to a wide array of molecularly distinct forms of damage, life has evolved multiple DNA repair and associated processes, collectively termed the DNA-damage response (DDR). The importance of DNA repair and other DDR mechanisms is underlined by their deregulation or loss causing cancer and various human genetic disorders. Work in my laboratory aims to decipher DDR mechanisms, particularly those triggered by DNA double-strand breaks. In my talk, I will begin by briefly summarising past work by me and my collaborators that led to the world's first registered DDR enzyme inhibitor drug - the PARP inhibitor olaparib/Lynparza. I will then describe some of our recent work using CRISPR-Cas9 genetic screens to discover new DDR factors/regulators, identify potential new avenues for anti-cancer therapy, and help us understand how cancer cells can evolve resistance to DNA-damaging chemotherapies, PARP inhibitors or other DDR enzyme inhibitors.

Citation Format: Stephen P. Jackson. Exploiting genome instability for new cancer therapies: PARP inhibitors and beyond [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr PL06-03.