ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 20; pp. 5576 - 5590
• Main Authors: Perkhofer, Lukas, Schmitt, Anna, Romero Carrasco, Maria Carolina, Ihle, Michaela, Hampp, Stephanie, Ruess, Dietrich Alexander, Hessmann, Elisabeth, Russell, Ronan, Lechel, André, Azoitei, Ninel, Lin, Qiong, Liebau, Stefan, Hohwieler, Meike, Bohnenberger, Hanibal, Lesina, Marina, Algül, Hana, Gieldon, Laura, Schröck, Evelin, Gaedcke, Jochen, Wagner, Martin, Wiesmüller, Lisa, Sipos, Bence, Seufferlein, Thomas, Reinhardt, Hans Christian, Frappart, Pierre-Olivier, Kleger, Alexander
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 15.10.2017
• Subjects: Adenocarcinoma; Animals; Apoptosis; Ataxia Telangiectasia Mutated Proteins - deficiency; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - enzymology; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Clonal deletion; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxyribonucleic acid; DNA; DNA Damage; Fluorouracil - pharmacology; Gene Expression; Genomes; Genomic Instability; Genotypes; Humans; Immunohistochemistry; Inhibitors; Lethality; Male; Mesenchyme; Mice; Mice, SCID; Mutation; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Phthalazines - pharmacology; Piperazines - pharmacology; Poly(ADP-ribose) polymerase; Tumorigenesis; Viability
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-17-0634

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 ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional 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 and 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. .