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

Aditi Jain, Lebaron C. Agostini, Grace A. McCarthy, Saswati N. Chand, Ann Josette Ramirez, Avinoam Nevler, Joseph Cozzitorto, Christopher W. Schultz, Cinthya Yabar Lowder, Kate M. Smith, Ian D. Waddell, Maria Raitses-Gurevich, Chani Stossel, Yulia Glick Gorman, Dikla Atias, Charles J. Yeo, Jordan M. Winter, Kenneth P. Olive, Talia Golan, Michael J. PishvaianDonald Ogilvie, Dominic I. James, Allan M. Jordan, Jonathan R. Brody

Research output: Contribution to journalArticlepeer-review

Abstract

Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have an average survival of less than 1 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 (PARGi), PDDX-01/04. Homologous repair-deficient cells compared with homologous repair-proficient cells were more sensitive to PARGi in vitro. In vivo, silencing of PARG significantly decreased tumor growth. PARGi synergized with DNA-damaging agents (i.e., oxaliplatin and 5-fluorouracil), but not with PARPi therapy. Mechanistically, combined PARGi and oxaliplatin treatment led to persistence of detrimental PARylation, increased expression of cleaved caspase-3, and increased gH2AX foci. In summary, these data validate PARG as a relevant target in PDAC and establish current therapies that synergize with PARGi.

Original languageEnglish (US)
Pages (from-to)4491-4502
Number of pages12
JournalCancer Research
Volume79
Issue number17
DOIs
StatePublished - Sep 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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