Targeting Poly (ADP) Ribose Glycohydrolase as a Combinatorial Strategy to Enhance DNA Damage in Gastrointestinal Cancers

Lebaron C Agostini, Thomas Jefferson University

Abstract

The DNA damage response (DDR) pathway sets the stage for tumorigenesis and provides both an opportunity for drug efficacy and resistance. Therapeutic approaches to target the DDR pathway include; increasing cytotoxic chemotherapies' effectiveness and creating synergistic drug strategies to enhance DNA damage and cell death. Here, we report combinatorial targeting of Poly (ADP) Ribose Glycohydrolase (PARG) with other DDR proteins and cytotoxic agents as a novel therapeutic strategy to enhance DNA damage in gastrointestinal tumors, namely pancreatic ductal adenocarcinoma (PDAC) and Colorectal Carcinoma (CRC) tumors. Small molecule inhibition and genetic silencing of PARG were used to evaluate synthetic lethality and create a novel DDR targeted synergy in cancer cells. We demonstrated that homologous recombination deficiency (HRD) cancer cells were more sensitive to PARG inhibition and that potent drug synergy arises from combining PARG inhibition with DNA damaging agents. Additionally, we demonstrated that the Wee1 checkpoint kinase inhibitor adavosertib (AZD1775) was synergistic with PARG inhibition in (PDAC) and (CRC) cells in vitro and in vivo. Mechanistically, combined PARG inhibition and oxaliplatin treatment led to the persistence of detrimental PARylation, increased expression of cleaved caspase-3, and increased γH2AX foci. We also show mechanistically that PARG inhibition enhances DNA damage and replication stress when combined with Wee1 inhibition, resulting in increased cell death and S-phase specific DNA damage. These findings validate PARG as a relevant target in PDAC and CRC tumors and establish novel therapeutic strategies for combining DNA damaging agents with PARG inhibitors to increase apoptosis in gastrointestinal (GI) cancer cells.

Subject Area

Cellular biology|Oncology|Biochemistry|Molecular biology

Recommended Citation

Agostini, Lebaron C, "Targeting Poly (ADP) Ribose Glycohydrolase as a Combinatorial Strategy to Enhance DNA Damage in Gastrointestinal Cancers" (2021). ETD Collection for Thomas Jefferson University. AAI28318299.
https://jdc.jefferson.edu/dissertations/AAI28318299

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