Abstract 546: PARG and WEE1 inhibition in GI cancers: A novel synergistic, targeted therapeutic approach
| Autor: | Jonathan R. Brody, Michael J. Pishvaian, Lebaron C. Agostini, Aditi Jain, Charles J. Yeo |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Cancer Research. 80:546-546 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Colorectal carcinomas (CRC) and pancreatic ductal adenocarcinomas (PDAC) are the 2nd and 3rd leading causes of cancer-related deaths in the U.S. respectively. Recent work from our lab highlighted Poly ADP-Ribose Glycohydrolase (PARG) as a target in PDAC, and PARG inhibition (PARGi) sensitized PDAC cells to the DNA damaging agents, 5-FU and oxaliplatin. Other labs have shown that PARG inhibition causes replication stress in cancer cells. CRC and PDAC cells, while cellularly different, share a high frequency of KRAS and P53 inactivating mutations. High levels of replication stress (RS) has also been well documented in these tumor types. Targeting DNA Damage Response Kinases (DDRKs) in combination with chemotherapy (mostly DNA damage inducers like 5-FU, oxaliplatin, etc.) has gained recent interest in solid tumors but overlapping toxicities and tolerability have been issues clinically. Accordingly, we hypothesized that combined inhibition of PARG and DDRKs could yield synergistic effects in tumors with high replication stress while alleviating adverse events seen in other combination strategies. We determined in drug sensitivity assays that PARGi did not synergize with either the CHK1 inhibitor prexasertib or the ATR inhibitor VE-821 in our cell lines but did synergize with Wee1i (AZD1775) in both PDAC and CRC cell lines (Comb. Analysis, p2-fold increases in PARylation, yH2AX, and cleaved-caspase 3 as compared to single-agent controls. In conclusion, combined PARG - Wee1 inhibition is a novel targeting strategy in PDAC and CRC tumors that results in decreased cell viability. We are currently testing the efficacy of AZD1775 in PARG CRISPR-knockout tumors in in vivo xenograft models. Ongoing studies are focused on assessing the effect of Wee1i + PARGi on chromosomal aberrations, disruption in replication fork dynamics via DNA fiber labeling, and cell cycle dependencies. Citation Format: Lebaron C. Agostini, Aditi Jain, Michael Pishvaian, Charles Yeo, Jonathan Brody. PARG and WEE1 inhibition in GI cancers: A novel synergistic, targeted therapeutic approach [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 546. |
| Databáze: | OpenAIRE |
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