Poly (ADP) ribose glycohydrolase can be effectively targeted in pancreatic cancer

Abstract

Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have an average survival of less than one year, underscoring the importance of evaluating novel targets with matched targeted agents. We recently identified that poly (ADP) ribose glycohydrolase (PARG) is a strong candidate target due to its dependence on the pro-oncogenic mRNA stability factor HuR (ELAVL1). Here, we evaluated PARG as a target in PDAC models using both genetic silencing of PARG and established small molecule PARG inhibitors, PDDX-001/004 (PARGi). Homologous repair-deficient cells compared to homologous repair-proficient cells were more sensitive to PARG inhibitors in vitro. In vivo, silencing of PARG significantly decreased tumor growth. PARGi synergized with DNA damaging agents (i.e., oxaliplatin and 5-FU), but not with PARP inhibitor therapy. Mechanistically, combined PARGi and oxaliplatin treatment led to persistence of detrimental PARylation, increased expression of cleaved caspase 3 and increased -H2AX foci. In summary, these data validate PARG as a relevant target in PDAC and establish current therapies that synergize with PARGi.