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Moon lab pursues development of novel therapeutics for breast, ovary, and prostate cancer

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> 
 > 
 > Date: 2021.12.28
> 
> Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality
> 
> Cancer Cell, Volume 33, Issue 6, 11 June 2018, Pages 1078-1093.e12
> 
> Highlights
> 
> • Endogenous PARG activity is crucial for the success of PARP inhibition therapy
> • PARG suppression restores downstream PARP1 signaling upon PARP inhibitor treatment
> • PARG depletion results in new vulnerabilities that can be exploited therapeutically
> • PARG-negative clones are pre-existing in cancers relevant for PARPi therapy
> 
> Summary
> 
> Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism. We also found the presence of PARG-negative clones in a subset of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Importantly, PARG inactivation exposes vulnerabilities that can be exploited therapeutically.
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