Combined Targeting of PARG and Wee1 Causes Decreased Cell Survival and DNA Damage in an S-Phase–Dependent Manner
| Autor: | Avinoam Nevler, Aditi Jain, Jonathan R. Brody, Alison B. Shupp, Karen M. Bussard, Charles J. Yeo, Lebaron C. Agostini, Grace A. McCarthy |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death Cell Survival DNA damage Mice Nude Cell Cycle Proteins Transfection medicine.disease_cause Article S Phase Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Gene silencing Molecular Biology PARG biology Kinase GTPase-Activating Proteins Protein-Tyrosine Kinases Xenograft Model Antitumor Assays Wee1 030104 developmental biology Oncology 030220 oncology & carcinogenesis biology.protein Cancer research Female Carcinogenesis DNA Damage |
| Zdroj: | Mol Cancer Res |
| ISSN: | 1557-3125 1541-7786 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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