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 - Funding Information:
a commercial research grant from Genisphere, LLC. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
G.A. McCarthy reports receiving a commercial research grant from Genisphere, LLC. T. Golan reports receiving a commercial research grant from MSD and AstraZeneca, has received speakers bureau honoraria from Abbvie, and is a consultant/advisory board member for Abbvie and Teva. D.I. James is a consultant for Cancer Research UK. J.R. Brody reports receiving
Funding Information:
We would like to thank Genisphere LLC (Dr. Robert Getts, Hatfield, PA) for providing us with the modified siPARG. Mark Levine's contributions to this work were made in memory of Ethel Levine. This work was supported by NIH-NCI R01 CA212600 (to J.R. Brody) and R37CA227865 (to J.M. Winter and J.R. Brody), and was also supported by the NCI of the NIH under Award Number P30CA056036 SKCC Core Grant (Thomas Jefferson University). Additional work is supported by a 2015 Pancreatic Cancer Action Network American Association for Cancer Research Acceleration Network Grant (15-90-25-BROD to J.R. Brody and M.J. Pishvaian). This work is also generously supported by a Mary Halinski Fellowship (to A. Nevler) and the W. Kim Foster Pancreatic Cancer Research Endowment. K.M. Smith, I.D. Waddell, D. Ogilvie, D.I. James, and A.M. Jordan are supported by Cancer Research UK (grants C480/A11411 and C5759/A17098).
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 -