Researchers at the University of Manchester suggests the first-in-class poly(ADP-ribose) glycohydrolase (PARG) inhibitor PDD00017273 has the potential to complement poly(ADP-ribose) polymerase (PARP) inhibitor strategies in the treatment of ovarian cancer.
The researchers showed that a subset of preclinical ovarian cancer models (OCMs), including established cell lines and ex vivo cultures derived from patient biopsies, are sensitive to pharmacological inhibition of PARG.
Furthermore, additional models were rendered sensitive when combined with therapeutic agents that induce replication stress, in particular an inhibitor targeting the DNA damage response checkpoint kinase CHK1.
The observations, presented in the journal Cancer Cell, suggest that sensitivity arises due to an underlying DNA replication vulnerability that renders cells dependent on PARG activity and on PARG inhibition, stalled DNA replication forks fail to restart, leading to persistent replication stress.
Because PARG and PARP inhibitor sensitivity are mutually exclusive, the findings demonstrate that PARG inhibitors have therapeutic potential to complement PARP inhibitor strategies in the treatment of ovarian cancer, the authors said.
Study author, Nisha Pillay, said the research shows that an inherent defect in the ability of an ovarian cancer cell to replicate its DNA can be exploited by PARG inhibitors.
"This new class of drugs is potentially very exciting and could signal a new way to help patients diagnosed with ovarian cancer in which their tumour has not responded to standard treatments."
