Poly (ADP) Ribose Glycohydrolase Can Be Effectively Targeted in Pancreatic Cancer.
Cancer Res
; 79(17): 4491-4502, 2019 09 01.
Article
em En
| MEDLINE
| ID: mdl-31273064
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 γH2AX foci. In summary, these data validate PARG as a relevant target in PDAC and establish current therapies that synergize with PARGi. SIGNIFICANCE:
PARG is a potential target in pancreatic cancer as a single-agent anticancer therapy or in combination with current standard of care.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Carcinoma Ductal Pancreático
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Glicosídeo Hidrolases
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article