TY  - JOUR
A1  - Fischer, Thomas
A1  - Hartmann, Oliver
A1  - Reissland, Michaela
A1  - Prieto-Garcia, Cristian
A1  - Klann, Kevin
A1  - Pahor, Nikolett
A1  - Schülein, Christina
A1  - Baluapuri, Apoorva
A1  - Polat, Bülent
A1  - Abazari, Arya
A1  - Gerhard-Hartmann, Elena Maria
A1  - Kopp, Hans-Georg
A1  - Eßmann, Frank
A1  - Rosenfeldt, Mathias Tillmann
A1  - Münch, Christian
A1  - Flentje, Michael
A1  - Diefenbacher, Markus Elmar
T1  - PTEN mutant non-small cell lung cancer require ATM to suppress pro-apoptotic signalling and evade radiotherapy
T2  - Cell & bioscience
N2  - 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.
KW  - ATM
KW  - Cancer
KW  - DNA-PK
KW  - IR
KW  - NSCLC
KW  - PI3K
KW  - PTEN
KW  - Radiotherapy
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/85708
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-857080
SN  - 2045-3701
N1  - 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.
N1  - 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.
N1  - Open Access funding enabled and organized by Projekt DEAL
VL  - 12
IS  - art. 50
SP  - 1
EP  - 22
PB  - BioMed Central
CY  - London
ER  -