Journal
CANCER RESEARCH
Volume 77, Issue 20, Pages 5576-5590Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-0634
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [2544/1-1, 2544/1-2]
- Forschungskern SyStaR
- BIU (Bohringer Ingelheim)
- NDIMED-Verbund PancChip
- Else-Kroner-Fresenius Stiftung [2011_A200]
- Else-Kroner-Fresenius Memorial funding
- Fritz-Thyssen Foundation [2015-00363]
- Deutsche Krebshilfe [111879, 111724]
- Baden-Wurttemberg Stiftung
- Else Kroner-Forschungskolleg Ulm
- Deutsche Forschungsgemeinschaft [AZ.961-3, KFO-286, 2254]
- Volkswagenstiftung (Lichtenberg Program)
- Bundesministerium fur Bildung und Forschung (SMOOSE)
- German federal state North Rhine Westphalia (NRW) as part of the EFRE initiative [LS-1-1-030a]
- Else Kroner-Fresenius Stiftung [EKFS-2014-A06]
- DFG Graduate School of Molecular Medicine at Ulm University
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Pancreatic ductal adenocarcinomas (PDAC) harbor recurrent functional mutations of the master DNA damage response kinase ATM, which has been shown to accelerate tumorigenesis and epithelial-mesenchymal transition. To study how ATMdeficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements, and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells in vitro and in vivo associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC. (C) 2017 AACR.
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