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

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

PROVIDER: PRJEB45803 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR6090790_1.fastq.gz	Fastqsanger.gz
	ERR6090790_2.fastq.gz	Fastqsanger.gz
	ERR6090791_1.fastq.gz	Fastqsanger.gz
	ERR6090791_2.fastq.gz	Fastqsanger.gz
	ERR6090784_1.fastq.gz	Fastqsanger.gz

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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

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

ATR inhibition enables complete tumour regression in ALK-driven NB mouse models

Project description:High-risk neuroblastoma (NB) often involves amplification of the neural MYC (MYCN) oncogene as well as mutations in ALK. Currently, high-risk NB presents significant clinical challenges, and additional therapeutic options are needed. Oncogenes such as MYCN and ALK result in increased replication stress in cancer cells, offering one such therapeutically exploitable option. Here, we followed up on earlier phosphoproteomic analyses that identified ATR activity in ALK-driven NB cell lines. We tested several ATR inhibitors, identifying BAY 1895344 as the most potent inhibitor of NB cell growth and proliferation. Using RNA-Seq, proteomics and phosphoproteomics we characterized the response of NB cells and tumours to ATR inhibition, identifying key components of the DNA damage response (DDR) as well as ATRX, MYCN, E2F and DCK among other ATR targets in NB cells. ATR inhibition with BAY 1895344 also produced robust responses in mouse NB models. Remarkably, a 2 week protocol combining ATR and ALK inhibition led to complete regression of NB tumours in two independent NB genetically modified mouse tumour models. These results suggest that NB patients, particularly in high-risk groups with oncogene induced replication stress, may benefit from inhibition of ATR as therapeutic intervention.

2021-11-02 | PXD027187 | Pride

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.

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

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

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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.

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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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Preclinical evaluation of the BET bromodomain inhibitor BAY 1238097 for the treatment of lymphoma

Project description:The epigenome is often deregulated in cancer and treatment with inhibitors of bromodomain and extra-terminal proteins, the readers of epigenetic acetylation marks, represents a novel therapeutic approach. Here, we have characterized the anti-tumour activity of the novel bromodomain and extra-terminal (BET) inhibitor BAY 1238097 in preclinical lymphoma mod- els. BAY 1238097 showed anti-proliferative activity in a large panel of lym- phoma-derived cell lines, with a median 50% inhibitory concentration between 70 and 208 nmol/l. The compound showed strong anti-tumour efficacy in vivo as a single agent in two diffuse large B cell lymphoma mod- els. Gene expression profiling showed BAY 1238097 targeted the NFKB/ TLR/JAK/STAT signalling pathways, MYC and E2F1-regulated genes, cell cycle regulation and chromatin structure. The gene expression profiling sig- natures also highly overlapped with the signatures obtained with other BET Bromodomain inhibitors and partially overlapped with HDAC-inhibitors, mTOR inhibitors and demethylating agents. Notably, BAY 1238097 presented in vitro synergism with EZH2, mTOR and BTK inhibitors. In conclusion, the BET inhibitor BAY 1238097 presented promising anti-lym- phoma preclinical activity in vitro and in vivo, mediated by the interference with biological processes driving the lymphoma cells. Our data also indicate the use of combination schemes targeting EZH2, mTOR and BTK along- side BET bromodomains.

2017-09-05 | GSE93032 | GEO

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

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

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IBL-302 PIM/PI3K/mTOR triple kinase inhibitor treatment of patient derived orthotopic xenograft neuroblastoma cells

Project description:neuroblastoma cells derived from PDOX models were treated with the kinase inhibitor.

2019-06-22 | GSE133137 | GEO