Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer
Johann Gout, Lukas Perkhofer, Mareen Morawe, Frank Arnold, Michaela A. Ihle, Stephanie Biber, Sebastian Lange, Élodie Roger, Johann M. Kraus, Katja Stifter, Stephan A. Hahn, Andrea Zamperone, Thomas Engleitner, Martin C. Müller, Karolin Walter, Eva Rodríguez-Aznar, Bruno Sáinz, Patrick Hermann, Elisabeth Heßmann, Sebastian A. Müller, Ninel Azoitei, André Lechel, Stefan Liebau, Martin Wagner, Diane M. Simeone, Hans A. Kestler, Thomas Seufferlein, Lisa Wiesmüller, Roland Rad, Pierre‐Olivier Frappart, Alexander Kleger
Abstract
OBJECTIVE: (ATM) is the most frequently mutated DNA damage response gene, involved in homologous recombination (HR), in pancreatic ductal adenocarcinoma (PDAC). DESIGN: Combinational synergy screening was performed to endeavour a genotype-tailored targeted therapy. 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. 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.