Functionally-instructed modifiers of response to ATR inhibition in experimental glioma
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PROVIDER: PRJNA955169 | ENA |
REPOSITORIES: ENA
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Project description:We investigated the influence of ATR inhibition by AZD6738 treatment in LN229 and LNZ308 glioma cells.
2024-03-22 | GSE229614 | GEO
Project description:BackgroundThe 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.MethodsWe 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.ResultsATRi 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.ConclusionIn conclusion, our study leads to the identification of novel combination therapies involving ATRi that could inform future preclinical studies and early phase clinical trials.
| S-EPMC10935927 | biostudies-literature
Project description:Global gene expression patterns were compared among wild-type Col-0, teb, atr, teb atr of A. thaliana using shoot apices.
2008-04-01 | E-MEXP-1329 | biostudies-arrayexpress
Project description:Registered systemic treatment options for glioblastoma patients are limited, particularly for progressive glioblastoma, including bevacizumab in the US and some other countries as well as lomustine. The phase II REGOMA trial suggested an improvement of overall survival in progressive glioblastoma by the multi-tyrosine kinase inhibitor regorafenib. This has not been confirmed by GBM AGILE, however. Of note, regorafenib has been administered as monotherapy in progressive glioblastoma or as an addition to standard of care in newly diagnosed glioblastoma. Rational combination therapies involving regorafenib, instead of entirely discontinuing any consideration of this compound, might be therefore a reasonable strategy. We addressed this research gap and used an innovative discovery and validation approach to identify functionally-instructed combination therapies. We applied a genome-wide CRISPR-Cas9-based functional genomics experimental approach including activation and knockout screens for the discovery of potential molecular targets modifying the therapeutic efficacy of regorafenib in experimental glioma. Selected functionally instructed molecular hits were then validated regarding synergistic interaction in vitro, ex vivo and in two orthotopic mouse models in vivo.This functional genomics approach led to the discovery of several molecular targets. Based on subsequent validation experiments including a customized compound library, we identified novel combination therapies. Particularly, the combination of regorafenib with Bcl-2/Bcl-xL inhibition was among the most promising strategies.
2024-08-21 | GSE272737 | GEO
Project description:Microcephaly and medulloblastoma result from mutations that compromise genomic stability. We report that Atr, which is mutated in the microcephalic disorder Seckel syndrome, is required to maintain chromosomal integrity during postnatal cerebellar neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis, and cerebellar hypoplasia. Co-deletions of either Bax and Bak or p53 prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. Atr-deficient CGNPs showed impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to Atr-deficient proliferation was p53-driven. Acute Atr inhibition in vivo by nanoparticle-formulated VE-822 reproduced the disruptions seen with Atr deletion. Our data show that p53-driven apoptosis and senescence, and non-apoptotic cell death redundantly limit growth in Atr-deficient progenitors. These overlapping mechanisms that suppress growth in Atr-disrupted CGNPs may be exploited for treatment of CGNP-derived medulloblastoma using Atr inhibition.
2016-09-01 | GSE85393 | GEO
Project description:Microcephaly and medulloblastoma result from mutations that compromise genomic stability. We report that Atr, which is mutated in the microcephalic disorder Seckel syndrome, is required to maintain chromosomal integrity during postnatal cerebellar neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis, and cerebellar hypoplasia. Co-deletions of either Bax and Bak or p53 prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. Atr-deficient CGNPs showed impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to Atr-deficient proliferation was p53-driven. Acute Atr inhibition in vivo by nanoparticle-formulated VE-822 reproduced the disruptions seen with Atr deletion. Our data show that p53-driven apoptosis and senescence, and non-apoptotic cell death redundantly limit growth in Atr-deficient progenitors. These overlapping mechanisms that suppress growth in Atr-disrupted CGNPs may be exploited for treatment of CGNP-derived medulloblastoma using Atr inhibition.
2016-09-01 | GSE83720 | GEO
Project description:High-risk human papillomaviruses (HPVs) constitutively activate the ataxia telangiectasia and Rad3-related (ATR) DNA damage response pathway for their replication. Although ATR has many reported functions, knowledge of how it regulates viral replication is limited. Most studies regarding ATR function focus on its roles in cell survival and initiation of DNA damage response. In this study, we examined whether the transcriptional regulatory properties directed by ATR are critical for HPV pathogenesis, and if so which downstream targets are important. Using RNA-seq approaches, we observed that ATR knockdown increases expression of many inflammatory genes. This mechanism is dependent on the p62/GATA4 signaling pathway.
2020-07-27 | GSE142482 | GEO
Project description:To characterize the downstream gene expression response following ATR inhibition, we performed RNA-Seq after treatment of CLB-BAR and CLB-GE neuroblastoma cells with 50 nM of the ATR inhibitor BAY 1895344 for 24h and 48h
2021-10-21 | E-MTAB-10603 | biostudies-arrayexpress
Project description:As a part of the project looking into the role of ATR in regulating replication initiation, we report the replication timing analysis of the U2OS cells treated with ATR kinase inhibitor AZD6738
2019-07-26 | GSE131018 | GEO
Project description:To understand the in vivo transcriptomic response to ATR inhibition, RNA-Seq was performed after treatment of 2 previously developed neuroblastoma mouse models (Alk-F1178S;Th-MYCN and Rosa26_Alkal2;Th-MYCN; see Borenas et al., EMBO J, 2021) with the ATR inhibitor BAY 1895344.
2021-10-21 | E-MTAB-10616 | biostudies-arrayexpress