Journal Article

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

Zamperone, Andrea, Müller, Sebastian, Rodriguez-Aznar, Eva, Simeone, Diane M, Lechel, André, Hahn, Stephan A, Stifter, Katja, Engleitner, Thomas, Roger, Elodie, Biber, Stephanie, Frappart, Pierre-Olivier, Morawe, Mareen, Lange, Sebastian, Perkhofer, Lukas, Walter, Karolin, Azoitei, Ninel, Seufferlein, Thomas, Kestler, Hans A, Hessmann, Elisabeth, Gout, Johann, Kleger, Alexander, Sainz Jr, Bruno, Wagner, Martin, Kraus, Johann M, Hermann, Patrick C, Liebau, Stefan, Ihle, Michaela, Müller, Martin, Rad, Roland, Arnold, Frank, Wiesmüller, Lisa

2021

Overview

ObjectiveATM serine/threonine kinase (ATM) is the most frequently mutated DNA damage response gene, involved in homologous recombination (HR), in pancreatic ductal adenocarcinoma (PDAC).DesignCombinational synergy screening was performed to endeavour a genotype-tailored targeted therapy.ResultsSynergy 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.ConclusionAnalysis 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.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adenocarcinoma / Adenocarcinoma - drug therapy / Adenocarcinoma - genetics / Animals / Apoptosis / Ataxia Telangiectasia Mutated Proteins - genetics / Carcinoma, Pancreatic Ductal - drug therapy / Carcinoma, Pancreatic Ductal - genetics / Cell Line, Tumor / Cell Survival / Chromosome 5 / Copy number / CRISPR / Deoxyribonucleic acid / DNA / DNA Copy Number Variations / DNA Damage / DNA Repair / DNA-dependent protein kinase / Drug dosages / drug resistance / Drug Resistance, Multiple - genetics / Drug Synergism / Epithelial-Mesenchymal Transition / Genes / Genotype / Genotypes / Homologous Recombination / Humans / Lethality / Medical prognosis / Mesenchyme / Mice / Mitosis / Mortality / Multidrug resistance / Mutation / p53 Protein / Pancreas / Pancreatic cancer / Pancreatic Neoplasms - drug therapy / Pancreatic Neoplasms - genetics / pancreatic tumours / Plasmids / Poly(ADP-ribose) polymerase / Poly(ADP-ribose) Polymerase Inhibitors - pharmacology / Prognosis / Protein kinase C / Protein-serine/threonine kinase / Software / Tumors