TY - JOUR
T1 - Poly (ADP) ribose glycohydrolase can be effectively targeted in pancreatic cancer
AU - Jain, Aditi
AU - Agostini, Lebaron C.
AU - McCarthy, Grace A.
AU - Chand, Saswati N.
AU - Ramirez, Ann Josette
AU - Nevler, Avinoam
AU - Cozzitorto, Joseph
AU - Schultz, Christopher W.
AU - Lowder, Cinthya Yabar
AU - Smith, Kate M.
AU - Waddell, Ian D.
AU - Raitses-Gurevich, Maria
AU - Stossel, Chani
AU - Gorman, Yulia Glick
AU - Atias, Dikla
AU - Yeo, Charles J.
AU - Winter, Jordan M.
AU - Olive, Kenneth P.
AU - Golan, Talia
AU - Pishvaian, Michael J.
AU - Ogilvie, Donald
AU - James, Dominic I.
AU - Jordan, Allan M.
AU - Brody, Jonathan R.
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-18-3645
DO - 10.1158/0008-5472.CAN-18-3645
M3 - Article
C2 - 31273064
AN - SCOPUS:85071784835
SN - 0008-5472
VL - 79
SP - 4491
EP - 4502
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -