PUBLICATION
Functionally-instructed modifiers of response to ATR inhibition in experimental glioma
- Authors
- Walter, B., Hirsch, S., Kuhlburger, L., Stahl, A., Schnabel, L., Wisser, S., Haeusser, L.A., Tsiami, F., Plöger, S., Aghaallaei, N., Dick, A.M., Skokowa, J., Schmees, C., Templin, M., Schenke-Layland, K., Tatagiba, M., Nahnsen, S., Merk, D.J., Tabatabai, G.
- ID
- ZDB-PUB-240313-19
- Date
- 2024
- Source
- Journal of experimental & clinical cancer research : CR 43: 7777 (Journal)
- Registered Authors
- Aghaallaei, Narges
- Keywords
- Combination therapies, DNA damage response pathway, DigiWest, Functional genomics
- MeSH Terms
-
- Animals
- Ataxia Telangiectasia Mutated Proteins/metabolism
- Cell Line, Tumor
- DNA Damage
- DNA Repair
- Glioma*
- Mice
- Zebrafish*
- PubMed
- 38475864 Full text @ J. Exp. Clin. Cancer Res.
Citation
Walter, B., Hirsch, S., Kuhlburger, L., Stahl, A., Schnabel, L., Wisser, S., Haeusser, L.A., Tsiami, F., Plöger, S., Aghaallaei, N., Dick, A.M., Skokowa, J., Schmees, C., Templin, M., Schenke-Layland, K., Tatagiba, M., Nahnsen, S., Merk, D.J., Tabatabai, G. (2024) Functionally-instructed modifiers of response to ATR inhibition in experimental glioma. Journal of experimental & clinical cancer research : CR. 43:7777.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping