Perkhofer, Lukas, Schmitt, Anna, Carrasco, Maria Carolina Romero, Ihle, Michaela, Hampp, Stephanie, Ruess, Dietrich Alexander, Hessmann, Elisabeth, Russell, Ronan, Lechel, Andre, Azoitei, Ninel, Lin, Qiong, Liebau, Stefan ORCID: 0000-0003-0721-8187, Hohwieler, Meike, Bohnenberger, Hanibal, Lesina, Marina, Alguel, Hana, Gieldon, Laura, Schroeck, Evelin, Gaedcke, Jochen, Wagner, Martin, Wiesmueller, Lisa, Sipos, Bence, Seufferlein, Thomas, Reinhardt, Hans Christian, Frappart, Pierre-Olivier and Kleger, Alexander (2017). ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage. Cancer Res., 77 (20). S. 5576 - 5591. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Perkhofer, LukasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carrasco, Maria Carolina RomeroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ihle, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hampp, StephanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruess, Dietrich AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hessmann, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Russell, RonanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lechel, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Azoitei, NinelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lin, QiongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liebau, StefanUNSPECIFIEDorcid.org/0000-0003-0721-8187UNSPECIFIED
Hohwieler, MeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bohnenberger, HanibalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lesina, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alguel, HanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gieldon, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeck, EvelinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gaedcke, JochenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagner, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiesmueller, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sipos, BenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seufferlein, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, Hans ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frappart, Pierre-OlivierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kleger, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-214220
DOI: 10.1158/0008-5472.CAN-17-0634
Journal or Publication Title: Cancer Res.
Volume: 77
Number: 20
Page Range: S. 5576 - 5591
Date: 2017
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1538-7445
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
REPAIR; PARP; RESISTANCE; INHIBITION; ROLES; P53; EVOLUTION; DISTINCT; STRESS; H2AXMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21422

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