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Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer
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). DESIGN: Combinational synergy screening was performed to endeavour a genotype-tailored targeted therapy. RESULT...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948173/ https://www.ncbi.nlm.nih.gov/pubmed/32873698 http://dx.doi.org/10.1136/gutjnl-2019-319970 |
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author | Gout, Johann Perkhofer, Lukas Morawe, Mareen Arnold, Frank Ihle, Michaela Biber, Stephanie Lange, Sebastian Roger, Elodie Kraus, Johann M Stifter, Katja Hahn, Stephan A Zamperone, Andrea Engleitner, Thomas Müller, Martin Walter, Karolin Rodriguez-Aznar, Eva Sainz Jr, Bruno Hermann, Patrick C Hessmann, Elisabeth Müller, Sebastian Azoitei, Ninel Lechel, André Liebau, Stefan Wagner, Martin Simeone, Diane M Kestler, Hans A Seufferlein, Thomas Wiesmüller, Lisa Rad, Roland Frappart, Pierre-Olivier Kleger, Alexander |
author_facet | Gout, Johann Perkhofer, Lukas Morawe, Mareen Arnold, Frank Ihle, Michaela Biber, Stephanie Lange, Sebastian Roger, Elodie Kraus, Johann M Stifter, Katja Hahn, Stephan A Zamperone, Andrea Engleitner, Thomas Müller, Martin Walter, Karolin Rodriguez-Aznar, Eva Sainz Jr, Bruno Hermann, Patrick C Hessmann, Elisabeth Müller, Sebastian Azoitei, Ninel Lechel, André Liebau, Stefan Wagner, Martin Simeone, Diane M Kestler, Hans A Seufferlein, Thomas Wiesmüller, Lisa Rad, Roland Frappart, Pierre-Olivier Kleger, Alexander |
author_sort | Gout, Johann |
collection | PubMed |
description | 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). 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. |
format | Online Article Text |
id | pubmed-7948173 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-79481732021-03-28 Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer Gout, Johann Perkhofer, Lukas Morawe, Mareen Arnold, Frank Ihle, Michaela Biber, Stephanie Lange, Sebastian Roger, Elodie Kraus, Johann M Stifter, Katja Hahn, Stephan A Zamperone, Andrea Engleitner, Thomas Müller, Martin Walter, Karolin Rodriguez-Aznar, Eva Sainz Jr, Bruno Hermann, Patrick C Hessmann, Elisabeth Müller, Sebastian Azoitei, Ninel Lechel, André Liebau, Stefan Wagner, Martin Simeone, Diane M Kestler, Hans A Seufferlein, Thomas Wiesmüller, Lisa Rad, Roland Frappart, Pierre-Olivier Kleger, Alexander Gut Pancreas 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). 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. BMJ Publishing Group 2021-04 2020-09-01 /pmc/articles/PMC7948173/ /pubmed/32873698 http://dx.doi.org/10.1136/gutjnl-2019-319970 Text en © 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. http://creativecommons.org/licenses/by-nc/4.0/ http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Pancreas Gout, Johann Perkhofer, Lukas Morawe, Mareen Arnold, Frank Ihle, Michaela Biber, Stephanie Lange, Sebastian Roger, Elodie Kraus, Johann M Stifter, Katja Hahn, Stephan A Zamperone, Andrea Engleitner, Thomas Müller, Martin Walter, Karolin Rodriguez-Aznar, Eva Sainz Jr, Bruno Hermann, Patrick C Hessmann, Elisabeth Müller, Sebastian Azoitei, Ninel Lechel, André Liebau, Stefan Wagner, Martin Simeone, Diane M Kestler, Hans A Seufferlein, Thomas Wiesmüller, Lisa Rad, Roland Frappart, Pierre-Olivier Kleger, Alexander Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer |
title | Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer |
title_full | Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer |
title_fullStr | Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer |
title_full_unstemmed | Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer |
title_short | Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer |
title_sort | synergistic targeting and resistance to parp inhibition in dna damage repair-deficient pancreatic cancer |
topic | Pancreas |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948173/ https://www.ncbi.nlm.nih.gov/pubmed/32873698 http://dx.doi.org/10.1136/gutjnl-2019-319970 |
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