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Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer.

Authors
  • Gout, Johann1
  • Perkhofer, Lukas1
  • Morawe, Mareen1
  • Arnold, Frank1
  • Ihle, Michaela2
  • Biber, Stephanie2
  • Lange, Sebastian3, 4, 5
  • Roger, Elodie1
  • Kraus, Johann M6
  • Stifter, Katja1
  • Hahn, Stephan A7
  • Zamperone, Andrea8, 9
  • Engleitner, Thomas3, 4
  • Müller, Martin1
  • Walter, Karolin1
  • Rodriguez-Aznar, Eva1
  • Sainz, Bruno Jr10, 11
  • Hermann, Patrick C1
  • Hessmann, Elisabeth12
  • Müller, Sebastian3, 4
  • And 11 more
  • 1 Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany. , (Germany)
  • 2 Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany. , (Germany)
  • 3 Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technische Universität München, Munich, Germany. , (Germany)
  • 4 Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technische Universität München, Munich, Germany. , (Germany)
  • 5 Department of Medicine II, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany. , (Germany)
  • 6 Institute of Medical Systems Biology, Ulm University, Ulm, Germany. , (Germany)
  • 7 Department of Molecular GI Oncology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany. , (Germany)
  • 8 Department of Surgery, NYU Langone Health, New York, NY, USA.
  • 9 Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
  • 10 Cancer Stem Cell and Tumor Microenvironment Group, Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, Madrid, Spain. , (Spain)
  • 11 Cancer Stem Cell and Fibroinflammatory Microenvironment Group, Area 3 - Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. , (Spain)
  • 12 Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, Göttingen, Germany. , (Germany)
  • 13 Institute of Neuroanatomy & Developmental Biology INDB, Eberhard Karls Universitat Tübingen, Tübingen, Germany. , (Germany)
  • 14 Department of Pathology, NYU Langone Health, New York, NY, USA.
  • 15 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. , (Germany)
  • 16 Institute of Toxicology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany. , (Germany)
  • 17 Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany [email protected] , (Germany)
Type
Published Article
Journal
Gut
Publisher
BMJ
Publication Date
Apr 01, 2021
Volume
70
Issue
4
Pages
743–760
Identifiers
DOI: 10.1136/gutjnl-2019-319970
PMID: 32873698
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

ATM serine/threonine kinase (ATM) is the most frequently mutated DNA damage response gene, involved in homologous recombination (HR), in pancreatic ductal adenocarcinoma (PDAC). Combinational synergy screening was performed to endeavour a genotype-tailored targeted therapy. Synergy was found on inhibition of PARP, ATR and DNA-PKcs (PAD) leading to synthetic lethality in ATM-deficient murine and human PDAC. Mechanistically, PAD-induced PARP trapping, replication fork stalling and mitosis defects leading to P53-mediated apoptosis. Most importantly, chemical inhibition of ATM sensitises human PDAC cells toward PAD with long-term tumour control in vivo. Finally, we anticipated and elucidated PARP inhibitor resistance within the ATM-null background via whole exome sequencing. Arising cells were aneuploid, underwent epithelial-mesenchymal-transition and acquired multidrug resistance (MDR) due to upregulation of drug transporters and a bypass within the DNA repair machinery. These functional observations were mirrored in copy number variations affecting a region on chromosome 5 comprising several of the upregulated MDR genes. Using these findings, we ultimately propose alternative strategies to overcome the resistance. Analysis of the molecular susceptibilities triggered by ATM deficiency in PDAC allow elaboration of an efficient mutation-specific combinational therapeutic approach that can be also implemented in a genotype-independent manner by ATM inhibition. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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