DNA replication stress and emerging prospects for PARG inhibitors in ovarian cancer therapy
AffiliationDivision of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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AbstractPoly (ADP-ribosyl)ation has central functions in maintaining genome stability, including facilitating DNA replication and repair. In cancer cells these processes are frequently disrupted, and thus interfering with poly (ADP-ribosyl)ation can exacerbate inherent genome instability and induce selective cytotoxicity. Indeed, inhibitors of poly (ADP-ribose) polymerase (PARP) are having a major clinical impact in treating women with BRCA-mutant ovarian cancer, based on a defect in homologous recombination. However, only around half of ovarian cancers harbour defects in homologous recombination, and most sensitive tumours eventually acquire PARP inhibitor resistance with treatment. Thus, there is a pressing need to develop alternative treatment strategies to target tumours with both inherent and acquired resistance to PARP inhibition. Several novel inhibitors of poly (ADP-ribose)glycohydrolase (PARG) have been described, with promising anti-cancer activity in vitro that is distinct from PARP inhibitors. Here we discuss, the role of poly (ADP-ribosyl)ation in genome stability, and the potential for PARG inhibitors as a complementary strategy to PARP inhibitors in the treatment of ovarian cancer.
CitationPillay N, Brady RM, Dey M, Morgan RD, Taylor SS. DNA replication stress and emerging prospects for PARG inhibitors in ovarian cancer therapy. Prog Biophys Mol Biol. 2021.
JournalProgress in Biophysics and Molecular Biology
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