Thomas Fischer, Oliver Hartmann, Michaela Reissland, Cristian Prieto-Garcia, Kevin Klann, Nikolett Pahor, Christina Schülein, Apoorva Baluapuri, Bülent Polat, Arya Abazari, Elena Maria Gerhard-Hartmann, Hans-Georg Kopp, Frank Eßmann, Mathias Tillmann Rosenfeldt, Christian Münch, Michael Flentje, Markus Elmar Diefenbacher
- Background: Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy.
Results: We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model.
Conclusion: PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.
MetadatenAuthor: | Thomas Fischer, Oliver HartmannORCiDGND, Michaela ReisslandORCiD, Cristian Prieto-GarciaORCiDGND, Kevin KlannORCiDGND, Nikolett Pahor, Christina SchüleinGND, Apoorva BaluapuriORCiDGND, Bülent PolatORCiDGND, Arya Abazari, Elena Maria Gerhard-HartmannORCiDGND, Hans-Georg KoppORCiDGND, Frank EßmannORCiDGND, Mathias Tillmann RosenfeldtORCiDGND, Christian MünchORCiDGND, Michael FlentjeGND, Markus Elmar DiefenbacherORCiD |
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URN: | urn:nbn:de:hebis:30:3-857080 |
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DOI: | https://doi.org/10.1186/s13578-022-00778-7 |
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ISSN: | 2045-3701 |
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Parent Title (English): | Cell & bioscience |
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Publisher: | BioMed Central |
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Place of publication: | London |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2022/04/27 |
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Date of first Publication: | 2022/04/27 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2024/06/04 |
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Tag: | ATM; Cancer; DNA-PK; IR; NSCLC; PI3K; PTEN; Radiotherapy |
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Volume: | 12 |
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Issue: | art. 50 |
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Article Number: | 50 |
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Page Number: | 22 |
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First Page: | 1 |
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Last Page: | 22 |
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Note: | The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
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Note: | Raw data is available via Mendeley Data https://doi.org/10.17632/6k8w3gb7z3.1. RNA-sequencing data is available at the Gene Expression Omnibus under the accession number GEO. |
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Note: | Open Access funding enabled and organized by Projekt DEAL |
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HeBIS-PPN: | 520853865 |
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Institutes: | Medizin |
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Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
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| 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - CC BY - Namensnennung 4.0 International |
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