Examining inhibitors of DNA repair as cancer therapy

Inhibitors of DNA repair have emerged as powerful agents in cancer therapy, either as monotherapies that exploit synthetic lethal interactions between DNA repair pathways, or by increasing the efficacy of chemo- and radiotherapies. Principal in this strategy is inhibition of Poly(ADP-ribose)-polymerases (PARPs), enzymes that regulate DNA strand break repair, and PARP inhibitors (PARPi) are being used to treat tumours with defects in homologous recombination (HR). However, this strategy is restricted to treating ovarian cancers, with limited information on why PARPi are toxic to HR-defective cells, or additional synthetic lethal interactions that will broaden their application to treat other tumours.

By combining our expertise in PARP biology and DNA repair (e.g. Ronson, et al. Nat Commun 9: 746) with cutting edge genome editing, proteomics and cell biology, this project will address this fundamentally important question by characterising novel cancer-related genes that are synthetic lethal with PARP dysfunction. Through a genome-wide CRISPR-Cas9 screen, we identified a novel gene (PASL9) that is synthetic lethal with PARPi. Our data indicate PASL9 is critical to resolve replication-associated DNA damage through a mechanism that is mutated in colorectal cancers. Through multidisciplinary hypothesis-driven research, this research will: a) Define the nature of synthetic lethality between PARPs and PASL9; b) Establish the repair mechanism regulated by PASL9; c) Assess PASL9 as a target to treat colorectal cancer. These studies will define the mechanistic basis of how PARPs and PASL9 maintain genome stability and define novel strategies to exploit PARPi to treat a variety of tumours.