Title |
ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage
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Published in |
Cancer Research, October 2017
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DOI | 10.1158/0008-5472.can-17-0634 |
Pubmed ID | |
Authors |
Lukas Perkhofer, Anna Schmitt, Maria Carolina Romero Carrasco, Michaela Ihle, Stephanie Hampp, Dietrich Alexander Ruess, Elisabeth Hessmann, Ronan Russell, André Lechel, Ninel Azoitei, Qiong Lin, Stefan Liebau, Meike Hohwieler, Hanibal Bohnenberger, Marina Lesina, Hana Algül, Laura Gieldon, Evelin Schröck, Jochen Gaedcke, Martin Wagner, Lisa Wiesmüller, Bence Sipos, Thomas Seufferlein, Hans Christian Reinhardt, Pierre-Olivier Frappart, Alexander Kleger |
Abstract |
Pancreatic adenocarcinomas (PDAC) harbour 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 ATM deficiency 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 1 | 20% |
Australia | 1 | 20% |
Unknown | 3 | 60% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 3 | 60% |
Scientists | 2 | 40% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 90 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 17 | 19% |
Student > Master | 12 | 13% |
Student > Ph. D. Student | 11 | 12% |
Student > Bachelor | 6 | 7% |
Other | 5 | 6% |
Other | 10 | 11% |
Unknown | 29 | 32% |
Readers by discipline | Count | As % |
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Biochemistry, Genetics and Molecular Biology | 23 | 26% |
Medicine and Dentistry | 19 | 21% |
Agricultural and Biological Sciences | 10 | 11% |
Social Sciences | 3 | 3% |
Immunology and Microbiology | 2 | 2% |
Other | 2 | 2% |
Unknown | 31 | 34% |