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DNA Damage Response Deficiency Enhances Neuroblastoma Progression and Sensitivity to Combination PARP and ATR Inhibition

ABSTRACT: DNA Damage Response Deficiency Enhances Neuroblastoma Progression and Sensitivity to Combination PARP and ATR Inhibition

PROVIDER: PRJNA1196438 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31668404_1.fastq.gz	Fastqsanger.gz
	SRR31668404_2.fastq.gz	Fastqsanger.gz
	SRR31668405_1.fastq.gz	Fastqsanger.gz
	SRR31668405_2.fastq.gz	Fastqsanger.gz
	SRR31668406_1.fastq.gz	Fastqsanger.gz

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DNA Damage Response Deficiency Enhances Neuroblastoma Progression and Sensitivity to Combination PARP and ATR Inhibition

Project description:Next generation sequencing of neuroblastoma (NB) tumors have revealed frequent somatic and germline genetic alterations in genes encoding proteins involved in DNA damage response (DDR) pathways. Despite being well-studied in many adult cancers, roles for DDR disruption in pediatric solid tumors have not been fully elucidated. To address this, patient-relevant loss-of-function mutations in DDR pathway components including Brca2, Atm, and Palb2 were incorporated into an established zebrafish MYCN transgenic model (Tg(dbh:EGFP-MYCN)). These mutations were found to enhance NB formation and metastasis in vivo, and result in upregulation of proliferation, cell cycle checkpoint and DNA damage repair transcriptional signatures, revealing novel molecular vulnerabilities in DDR-deficient NB. Zebrafish DDR-deficient NB and human NB cells with DDR protein knock-down were sensitive to the poly(ADP-ribose)-polymerase (PARP) inhibitor olaparib, and this effect was further enhanced by inhibition of the ataxia telangiectasia and rad3 related (ATR) kinase. Altogether, our data supports a functional role for DDR-deficiency in NB in vivo and therapeutic potential for combination PARP + ATR inhibition in NB patients with alterations in DDR genes.

2025-02-10 | GSE283976 | GEO

RNA-seq of human neuroblastoma cell lines treated with the ATR inhibitor BAY 1895344

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

RNA-seq of neuroblastoma mice models after treatment with the ATR inhibitor BAY 1895344

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

Deletion of 11q in neuroblastomas drives sensitivity to PARP inhibition [SEQ]

Project description:SNP arrays were combined with next generation sequencing (NGS) to precisely define the deleted region in 17 primary 11q-loss neuroblastomas and identify allelic variants in genes relevant for neuroblastoma aetiology. We assessed PARP inhibitor olaparib in combination with other chemotherapy medications using both in vitro and in vivo models.

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Deletion of 11q in neuroblastomas drives sensitivity to PARP inhibition [SNP array]

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RNA-seq of neuroblastoma mouse model (Alk-F1178S;Th-MYCN) after treatment with the ATR inhibitor ceralasertib

Project description:To understand the in vivo transcriptomic response to ATR inhibition, RNA-Seq was performed 3 days after treatment of a previously developed neuroblastoma mouse model (Alk-F1178S;Th-MYCN; see Borenas et al., EMBO J, 2021) with the ATR inhibitor ceralasertib.

2023-11-30 | E-MTAB-12961 | biostudies-arrayexpress

ALK signalling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition

Project description:High-risk neuroblastoma (NB) currently presents significant clinical challenges. MYCN and ALK, which are often involved in high-risk NB, lead to increased replication stress in cancer cells, providing options for therapeutic exploitation. We previously identified an ATR/ALK inhibitor combination as an effective therapeutic approach in two independent genetically modified mouse NB models. Here, we identify an underlying molecular mechanism, in which ALK signalling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. The importance of ALK inhibition is supported by mouse data, in which monotreatment with ATRi resulted in a robust initial response, but subsequent relapse, in contrast to a 14-day ALKi/ATRi combination treatment that resulted in robust and sustained responses. Finally, we show that the remarkable response to the 14-day combined ATR/ALK inhibition protocol reflects a robust differentiation response in the tumour, reprogramming tumour cells to a neuronal/Schwann cell lineage identity. Our results identify a unique ability of ATR inhibition to trigger neuroblastoma differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.

2023-12-13 | PXD041824 | Pride

Nuclear pCHK1 as a potential biomarker of increased sensitivity to ATR inhibition

Project description:Excessive genomic instability coupled with abnormalities in DNA repair pathways induce high levels of “replication stress” when cancer cells propagate. Rather than hampering cancer cell proliferation, novel treatment strategies are turning their attention toward targeting cell cycle checkpoint kinases (such as ATR, CHK1, WEE1 and others) along the DNA damage response and replicative stress response pathways, thereby allowing unrepaired DNA damage to be carried forward towards mitotic catastrophe and apoptosis. The selective inhibitor of ATR kinase elimusertib (BAY 1895344), has demonstrated preclinical and clinical monotherapy activity; however, reliable predictive biomarkers of treatment benefit are still lacking. In this study, using gene expression profiling of 24 cell lines from different cancer types and in a panel of ovarian cancer cell lines, we found that nuclear-specific enrichment of checkpoint kinase 1 (CHK1) correlated with increased sensitivity to elimusertib. Using an advanced multispectral imaging system in subsequent cell line-derived xenograft specimens, we showed a trend between nuclear phosphorylated-CHK1 (pCHK1) staining and increased sensitivity to the ATR inhibitor elimusertib, indicating the potential value of pCHK1 expression as a predictive biomarker of ATR inhibitor sensitivity.

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Project description:DNA Damage Response Deficiency Enhances Neuroblastoma Progression and Sensitivity to Combination PARP and ATR Inhibition

| PRJNA1214744 | ENA

PBRM1 deficiency is synthetic lethal with PARP inhibitors in human cancers

Project description:Polybromo-1 (PBRM1), which encodes a specific subunit of the pBAF chromatin remodeling complex, is inactivated in multiple malignancies including 50% of clear cell renal cell carcinoma. At present, a therapeutic strategy that selectively targets PBRM1 defects does not exist. PBRM1 is involved in multiple cellular processes including transcription, replication and DNA repair. Using high-throughput screens and multiple isogenic and non-isogenic models, we found that PBRM1 defects cause synthetic lethality with several clinical PARP inhibitors, both in vitro and in vivo. This effect was enhanced using combinations with either small molecule ATR or BET inhibitors. Mechanistically, PBRM1 defects caused increased replication stress, R-loop formation and genomic instability that was exacerbated by PARP inhibitors. We also found that PARP and ATR inhibitors activate the cGAS-STING innate immunity pathway in PBRM1-deficient but not in PBRM1-proficient cells. These data provide the pre-clinical rationale for assessing PARP inhibitors as a monotherapy or in combination with ATR inhibitors or immune checkpoint inhibitors, in patients with PBRM1-deficient cancers.

2022-02-21 | PXD017826 | Pride

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