PARG is a significant molecular target for treating PAR-related cancers. This review provides a comprehensive overview of the physiological role of PARG and the development of its inhibitors, highlighting its potential as an innovative target for cancer treatment.

Regardless of the BRCA/HRD-status, the induction of ssGAPs in preclinical models of ovarian cancer cells correlates with PARGi sensitivity. Patient-derived organoids (PDOs) may be a useful model system for testing PARGi sensitivity and functional biomarkers.

P1, N=216, Recruiting, IDEAYA Biosciences | N=68 --> 216 | Trial completion date: Sep 2025 --> May 2027 | Trial primary completion date: Jun 2025 --> Oct 2026

Finally, we find that PARP1 nuclear aggregates were highly persistent and were associated with cleaved cytoplasmic PARP1, ultimately leading to cell death. Overall, our data uncover an unexpected mechanism of PARG inhibitor cytotoxicity, which will shed light on the use of these drugs as anti-cancer therapeutics.

P1, N=112, Not yet recruiting, Danatlas Pharmaceuticals Co., Ltd

IU1-248 promotes NHEJ repair through the downregulation of the expression of c-Myc. USP14 inhibition may be a plausible strategy for expanding the utility of PARG inhibitors in TNBC in BRCA-mutant, PARP inhibitor-resistant settings.

In addition, we show that inhibition of thymidylate synthase, an enzyme required for dNTP homeostasis, induces PARG-dependency. Together, these observations suggest that PARG inhibitor sensitivity reflects an inability to control replisome speed and/or maintain helicase-polymerase coupling in response to nucleotide imbalances.

The standard treatment for GBM includes radiation combined with temozolomide, an alkylating agent...However, the overproduction of 2-hydroxyglutarate, an oncometabolite produced by the IDH1 R132H mutant protein, suppresses BER capacity by reducing Polβ protein levels. This defines a novel mechanism by which the IDH1 mutation in gliomas confers cellular sensitivity to alkylating agents and to inhibitors of the poly-ADP-ribose glycohydrolase, PARG.

P1, N=48, Recruiting, 858 Therapeutics, Inc.

P1, N=68, Recruiting, IDEAYA Biosciences

Combining PARG inhibitor (PARGi) and Temozolomide (TMZ) in IDH mutant cells leads to imbalanced NAD sequestration into PAR, causing metabolic lethality...In summary, this study demonstrates that the combination of PARGi and radiation regulates DNA repair pathways, augmenting cytotoxicity specifically in IDH mutant gliomas. Targeting PAR during radiation holds promise for treating IDH mutant gliomas, tailoring therapy to maximize durability while minimizing impact on normal cells.

P1, N=68, Recruiting, IDEAYA Biosciences | Not yet recruiting --> Recruiting

P1, N=68, Not yet recruiting, IDEAYA Biosciences

Moreover, studies in cell lines, tumors and tissues revealed that dose and time-dependent accumulation of PAR chains serves as a robust proximal pharmacodynamic biomarker indicative of PARG target engagement. IDE161 is a novel targeted therapy that exploits the synthetic lethal relationship between PARG and genomic instability, thus leading to selective anti-proliferative effects in tumors harboring defects in the HR pathway.

Our findings suggest that the mutated PARG acquires PDD00017273 resistance due to structural modifications. In addition, our findings indicate that PDD00017273 resistance induces mutation and PARP downregulation. These discoveries collectively provide a better understanding of the anticancer candidate PARG inhibitors in terms of resistance mechanisms and anticancer strategies.

We found that administration of the NAD precursor dihydronicotinamide riboside (NRH) to raise cellular NAD levels combined with PARG inhibition (PARGi) triggers hyperaccumulation of poly(ADP-ribose) (PAR), resulting from both DNA damage-induced and replication-stress-induced PARP1 activation. Furthermore, NRH promotes hyperaccumulation of PAR in the presence of TMZ and PARGi. This combination strongly suppresses the cell growth of GBM cells depleted of MSH6 or cells expressing MGMT, suggesting that this regimen may improve the efficacy of TMZ to overcome treatment resistance in GBM.

PARG can act as an oncogene in HCC by modulating PARG/DDB1/c-Myc signaling and could be used as a biomarker to identify patients with HCC who may benefit from anti-PD-1 treatment. Our findings suggest that coinhibition of PARG and PD-1 is an effective novel combination strategy for HCC patients.

Supplementation with the NAD precursor dihydronicotinamide riboside (NRH) rapidly increased NAD levels in GSCs and glioma cells, inducing PARP1 activation and mild suppression of replication fork progression...PAR accumulation is regulated by select PARP1- and PAR-interacting proteins. The involvement of XRCC1 highlights the base excision repair pathway in responding to replication stress while enhanced interaction of PARP1 with PCNA, RPA and ORC2 upon PAR accumulation implicates replication associated PARP1 activation and assembly with pre-replication complex proteins upon initiation of replication arrest, the intra S-phase checkpoint and the onset of apoptosis.

We discover that a subset of ovarian cancers are intrinsically sensitive to pharmacological PARG blockade, including drug-resistant disease, underpinned by a common mechanism of replication catastrophe. We explore the use of a transcript-based biomarker, and provide insight into the design of future clinical trials of PARGi in patients with ovarian cancer. However, our results highlight the complexity of developing a predictive biomarker for PARGi sensitivity.

Using cellular proliferation assays and xenograft models, we find that PARGi increases the cellular levels of PAR and significantly decreases the viability of HR-deficient cancer cell lines. Furthermore, inhibition of cell proliferation by PARGi is antagonized by PARPi, which is consistent with an on-target cellular mechanism of action (MOA). In conclusion, PARGi induces significant accumulation of PAR chains and decreases cell proliferation both in vitro and in vivo in HR-deficient tumor cells.