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Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma

ABSTRACT: Whole genome sequencing of ATRX / TP53 knockdown clones of the neuroblastoma cell line SK-N-SH

PROVIDER: EGAS00001004550 | EGA |

REPOSITORIES: EGA

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Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma.

Project description:BackgroundIn neuroblastoma, genetic alterations in ATRX, define a distinct poor outcome patient subgroup. Despite the need for new therapies, there is a lack of available models and a dearth of pre-clinical research.MethodsTo evaluate the impact of ATRX loss of function (LoF) in neuroblastoma, we utilized CRISPR-Cas9 gene editing to generate neuroblastoma cell lines isogenic for ATRX. We used these and other models to identify therapeutically exploitable synthetic lethal vulnerabilities associated with ATRX LoF.FindingsIn isogenic cell lines, we found that ATRX inactivation results in increased DNA damage, homologous recombination repair (HRR) defects and impaired replication fork processivity. In keeping with this, high-throughput compound screening showed selective sensitivity in ATRX mutant cells to multiple PARP inhibitors and the ATM inhibitor KU60019. ATRX mutant cells also showed selective sensitivity to the DNA damaging agents, sapacitabine and irinotecan. HRR deficiency was also seen in the ATRX deleted CHLA-90 cell line, and significant sensitivity demonstrated to olaparib/irinotecan combination therapy in all ATRX LoF models. In-vivo sensitivity to olaparib/irinotecan was seen in ATRX mutant but not wild-type xenografts. Finally, sustained responses to olaparib/irinotecan therapy were seen in an ATRX deleted neuroblastoma patient derived xenograft.InterpretationATRX LoF results in specific DNA damage repair defects that can be therapeutically exploited. In ATRX LoF models, preclinical sensitivity is demonstrated to olaparib and irinotecan, a combination that can be rapidly translated into the clinic.FundingThis work was supported by Christopher's Smile, Neuroblastoma UK, Cancer Research UK, and the Royal Marsden Hospital NIHR BRC.

| S-EPMC7452577 | biostudies-literature

Loss of p53 suppresses replication stress-induced DNA damage in ATRX-deficient neuroblastoma

Project description:To elucidate ATRX-dependent transcriptional alterations and their functional consequences, we performed a microarray analysis of Ctrl and ATRX KO NGP cells.

2022-09-08 | GSE183648 | GEO

ATRX mutant neuroblastoma is sensitive to EZH2 inhibition via modulation of neuronal differentiation

Project description:We report on the characterization of ATRX in-frame fusion neuroblastoma and identify that ATRX IFF proteins re-locate from H3K9me3 enriched regions to active chromatin, such as the promoter of neural repressor REST. We further identify that REST is upregulated in ATRX IFF NB and that several neurogenesis and REST target genes are transcriptionally downregulated. Through ChIP-seq analysis, we observe that REST is bound to ATRX IFF Down genes, which have higher levels of H3K27me3. We further show that ATRX in-frame fusion neuroblastoma cells are sensitive to EZH2 inhibitors through de-repression of H3K27me3 bound neuronal function genes, includiing a subset of REST targets.

2019-10-15 | GSE100148 | GEO

289449e8-9739-4fae-a3d5-15fdccfb5f72 - samples

Project description:Whole genome sequencing data of isogenic ATRX/TP53 knockout clones of the neuroblastoma cell line SK-N-SH

| EGAD00001006294 | EGA

Two opposing gene expression patterns within ATRX aberrant neuroblastoma

Project description:To study the role of distinct ATRX aberrations in neuroblastoma we created isogenic ATRX aberrant models using CRISPR-Cas9 in several neuroblastoma cell lines and one tumoroid. We created ATRX knock-out models, ATRX in-frame exon 2-10 deletions and ATRX in-frame exon 2-13 deletions. Additionally, we included patient-derived models data (i.e. cell line data and one tumoroid).

2023-03-16 | GSE226770 | GEO

Transcriptome analysis of SH-SY5Y and SK-N-AS neuroblastoma cells with KIT gene knockdown

Project description:The goal of this study was to identify dynamic changes in signaling pathway activities after KIT knockdown by RNAi in neuroblastoma with relatively high KIT expression (SH-SY5Y) and low expression (SK-N-AS).

2018-06-23 | GSE116175 | GEO

Transcriptomes in Human neuroblastoma cell line SH-SY5Y depleted with ERRαlpha and ERRgamma

Project description:The SH-SY5Y Human neuroblastoma cell line was subcloned from the SK-N-SH cell line, which has been isolated from a bone marrow biopsy of a 4 year-old female patient. To examine the overall distribution of gene expression under stress condition in human neuronal cells, we investigated changes in the transcriptome profiles in the SH-SY5Y cells depleted with ERRαlpha and ERRgamma by gene knockdown. We detected changes in the expression levels for several genes.

2024-08-20 | GSE208270 | GEO

DAC Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma

Project description:Data Access Committee EGAC00001001675

| EGAC00001001675 | EGA

Impaired gene expression in ATRX-depleted cells following interferon signaling

Project description:We investigated the role of the chromatin remodeling protein ATRX on ISG expression upon stimulation with IFN-β utilizing doxycycline-inducible ATRX knockdown cells.

2022-08-03 | GSE194396 | GEO

Alterations in chromatin accessibility in ATRX-depleted cells following interferon signaling

Project description:We investigated the role of the chromatin remodeling protein ATRX on chromatin accessibility specifically upon IFN-β stimulation utilizing stable ATRX knockdown cells.

2022-08-03 | GSE194395 | GEO

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