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Functionally-instructed modifiers of response to ATR inhibition in experimental glioma
Bianca Walter1,2, Sophie Hirsch1,2, Laurence Kuhlburger1,2,3,4
1Department of Neurology & Interdisciplinary Neuro-Oncology, University Hospital Tübingen, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
Background:
The DNA damage response (DDR) is a physiological network preventing malignant transformation, e.g. by halting cell cycle progression upon DNA damage detection and promoting DNA repair. Glioblastoma are incurable primary tumors of the nervous system and DDR dysregulation contributes to acquired treatment resistance. Therefore, DDR targeting is a promising therapeutic anti-glioma strategy. Here, we investigated Ataxia telangiectasia and Rad3 related (ATR) inhibition (ATRi) and functionally-instructed combination therapies involving ATRi in experimental glioma.
Methods:
We used acute cytotoxicity to identify treatment efficacy as well as RNAseq and DigiWest protein profiling to characterize ATRi-induced modulations within the molecular network in glioma cells. Genome-wide CRISPR/Cas9 functional genomic screens and subsequent validation with functionally-instructed compounds and selected shRNA-based silencing were employed to discover and investigate molecular targets modifying response to ATRi in glioma cell lines in vitro, in primary cultures ex vivo and in zebrafish and murine models in vivo.
Results:
ATRi monotherapy displays anti-glioma efficacy in vitro and ex vivo and modulates the molecular network. We discovered molecular targets by genome-wide CRISPR/Cas9 loss-of-function and activation screens that enhance therapeutic ATRi effects. We validated selected druggable targets by a customized drug library and functional assays in vitro, ex vivo and in vivo.
Conclusion:
In conclusion, our study leads to the identification of novel combination therapies involving ATRi that could inform future preclinical studies and early phase clinical trials.
Insights
Targeting the DNA damage response (DDR) with Ataxia telangiectasia and Rad3 related (ATR) inhibition shows promise for glioblastoma treatment. Novel combination therapies involving ATR inhibition were identified to enhance anti-glioma efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The DNA damage response (DDR) network is crucial for preventing cancer by managing DNA repair and cell cycle arrest.
- Dysregulation of the DDR pathway in glioblastoma contributes to treatment resistance, highlighting DDR-targeting as a therapeutic strategy.
- Ataxia telangiectasia and Rad3 related (ATR) inhibition (ATRi) is explored as a potential anti-glioma therapy.
Purpose of the Study:
- To investigate the efficacy of ATR inhibition (ATRi) as a monotherapy and in combination for experimental glioma.
- To identify molecular targets that can enhance the therapeutic effects of ATRi in glioma.
- To validate novel combination strategies for preclinical and clinical development.
Main Methods:
- Cytotoxicity assays, RNA sequencing, and DigiWest protein profiling were used to assess ATRi efficacy and molecular changes.
- Genome-wide CRISPR/Cas9 screens identified molecular targets modulating ATRi response.
- Validation was performed using functional assays, shRNA, and drug libraries in various glioma models (in vitro, ex vivo, in vivo).
Main Results:
- ATRi monotherapy demonstrated anti-glioma activity and altered the molecular landscape in glioma cells.
- CRISPR/Cas9 screens successfully identified molecular targets that potentiate the therapeutic effects of ATRi.
- Validated targets and combination therapies showed efficacy across in vitro, ex vivo, and in vivo models.
Conclusions:
- The study identified novel combination therapies involving ATRi for glioblastoma.
- These findings provide a basis for future preclinical studies and early-phase clinical trials targeting glioma.
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