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dc.contributor.authorGout, Johann-
dc.contributor.authorPerkhofer, Lukas-
dc.contributor.authorMorawe, Mareen-
dc.contributor.authorArnold, Frank-
dc.contributor.authorIhle, Michaela-
dc.contributor.authorBiber, Stephanie-
dc.contributor.authorLange, Sebastian-
dc.contributor.authorRoger, Elodie-
dc.contributor.authorKraus, Johann M.-
dc.contributor.authorStifter, Katja-
dc.contributor.authorHahn, Stephan A.-
dc.contributor.authorZamperone, Andrea-
dc.contributor.authorEngleitner, Thomas-
dc.contributor.authorMüller, Martin-
dc.contributor.authorWalter, Karolin-
dc.contributor.authorRodriguez-Aznar, Eva-
dc.contributor.authorSainz, Bruno Jr.-
dc.contributor.authorHermann, Patrick C.-
dc.contributor.authorHessmann, Elisabeth-
dc.contributor.authorMüller, Sebastian-
dc.contributor.authorAzoitei, Ninel-
dc.contributor.authorLechel, André-
dc.contributor.authorLiebau, Stefan-
dc.contributor.authorWagner, Martin-
dc.contributor.authorSimeone, Diane M.-
dc.contributor.authorKestler, Hans A.-
dc.contributor.authorSeufferlein, Thomas-
dc.contributor.authorWiesmüller, Lisa-
dc.contributor.authorRad, Roland-
dc.contributor.authorFrappart, Pierre-Olivier-
dc.contributor.authorKleger, Alexander-
dc.identifier.citationGut 0: 1-18 (2020)-
dc.description© Author(s) (or their employer(s)) 2020.-
dc.description.abstract[Objective]: ATM serine/threonine kinase (ATM) is the most frequently mutated DNA damage response gene, involved in homologous recombination (HR), in pancreatic ductal adenocarcinoma (PDAC).-
dc.description.abstract[Design]: Combinational synergy screening was performed to endeavour a genotype-tailored targeted therapy.-
dc.description.abstract[Results]: 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.-
dc.description.abstract[Conclusion]: 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.-
dc.description.sponsorshipMain funding is provided by the German Cancer Aid grant to AK (111879). Additional funding came from the Deutsche Forschungsgemeinschaft (DFG) ’Sachbeihilfe’ (KL 2544/1–1, 1–2, 5–1, 7-1) and ’Heisenberg-Programm’ (KL 2544/6–1), the Baden-Württemberg-Foundation ExPoChip and the INDIMEDVerbund PancChip. AK, FA, MI, SB, LW and TS are either Principal Investigators or students of HEIST RTG funded by the DFG GRK 2254/1. AK is an Else-KrönerFresenius Excellence fellow. LP received funds by the Bausteinprogramm of Ulm University. PCH is supported by a Max Eder Fellowship of the German Cancer Aid (111746), a German Cancer Aid Priority Program ’Translational Oncology’ 70112505 and by a Collaborative Research Centre grant (316249678 – SFB 1279) of the German Research Foundation. EH received funding from the German Cancer Aid (PiPAC, 70112505) and the Volkswagenstiftung/Ministry for Science and Culture in Lower Saxony (ZN3222). This work was also supported by the Deutsche Forschungsgemeinschaft (AZ.96/1–3) to NA, by the Deutsche Krebshilfe (111264) to AL and by the German Cancer Aid Priority Program Translational Oncology (70112504) to LW.-
dc.publisherBMJ Publishing Group-
dc.titleSynergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer-
dc.contributor.funderGerman Cancer Aid-
dc.contributor.funderGerman Research Foundation-
dc.contributor.funderUlm University-
dc.contributor.funderMinistry for Science and Culture of Lower Saxony-
dc.contributor.funderDeutsche Krebshilfe-
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