Poly (ADP) ribose glycohydrolase can be effectively targeted in pancreatic cancer
Authors
Jain, AAgostini, LC
McCarthy, GA
Chand, SN
Ramirez, A
Nevler, A
Cozzitorto, J
Schultz, CW
Lowder, CY
Smith, Kate M
Waddell, Ian D
Raitses-Gurevich, M
Stossel, C
Gorman, YG
Atias, D
Yeo, CJ
Winter, JM
Olive, KP
Golan, T
Pishvaian, MJ
Ogilvie, Donald J
James, Dominic I
Jordan, Allan M
Brody, JR
Affiliation
Department of Surgery, Thomas Jefferson UniversityIssue Date
2019
Metadata
Show full item recordAbstract
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.Citation
Jain A, Agostini LC, McCarthy GA, Chand SN, Ramirez A, Nevler A, et al. Poly (ADP) ribose glycohydrolase can be effectively targeted in pancreatic cancer. Cancer Res. 2019 Jul 4.Journal
Cancer ResearchDOI
10.1158/0008-5472.CAN-18-3645PubMed ID
31273064Additional Links
https://dx.doi.org/10.1158/0008-5472.CAN-18-3645Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1158/0008-5472.CAN-18-3645
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