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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 aiming to increase the efficacy of cytotoxic chemotherapies and synergistic drug strategies to enhance DNA damage, and hence cell death. Here, we report the first preclinical evaluation of a novel synergistic approach by using both genetic and small-molecule inhibition methods of silencing the DDR-related protein, poly (ADP-ribose) glycohydrolase (PARG), and the checkpoint kinase inhibitor, Wee1, in pancreatic ductal adenocarcinoma (PDAC) and colorectal carcinoma cells in vitro and in vivo . Mechanistically, we demonstrate that coinhibition of PARG and Wee1 synergistically decreased cell survival and increased DNA damage in an S-phase-dependent manner. IMPLICATIONS: In preclinical models, we demonstrate the efficacy and mechanism of action of targeting both PARG and Wee1 in PDAC and colorectal carcinoma cells. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/2/207/F1.large.jpg.

Combined Targeting of PARG and Wee1 Causes Decreased Cell Survival and DNA Damage in an S-Phase–Dependent Manner