GEO series

Cell context is the third axis of synergy for ATR inhibition and cisplatin in Ewing sarcoma

GSE260602 Homo sapiens (human) ChIP-seq / ATAC-seq (genome binding and open chromatin) 2 samples Submitted 2024/03/13 Platform GPL24676

At a glance

ChIP-seq / ATAC-seq (genome binding and open chromatin) · human · 2 samples

What it is: ChIP-seq / ATAC-seq (genome binding and open chromatin)Where proteins bind the genome, or which regions are open and active.
Organism: Homo sapiens (human)
Topic: Ewing sarcomaThis series is part of our curated briefing on it.
Samples: 2 samples
Data you can get: A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper: Cell Context Is the Third Axis of Synergy for the Combination of ATR Inhibition and Cisplatin in Ewing SarcomaClinical cancer research : an official journal of the American Association for Cancer Research · 2024

Summary (written by the submitters)

Purpose: The importance of cellular context to the synergy of DNA Damage Response (DDR) targeted agents is important for tumors with mutations in DDR pathways, but less well-established for tumors driven by oncogenic transcription factors. In this study, we exploit the widespread transcriptional dysregulation of the EWS-FLI1 transcription factor to identify an effective DDR targeted combination therapy for Ewing Sarcoma (ES).

Read the full summary ↓

Experimental Design: We used matrix drug screening to evaluate synergy between a DNA-PK inhibitor (M9831) or an ATR inhibitor (berzosertib) and chemotherapy. The combination of berzosertib and cisplatin was selected for broad synergy, mechanistically evaluated for ES selectivity, and optimized for in vivo schedule. Results: Berzosertib combined with cisplatin demonstrates profound synergy in multiple ES cell lines at clinically achievable concentrations. The synergy is due to loss of expression of the ATR downstream target CHEK1, loss of cell cycle checkpoints, and mitotic catastrophe. Consistent with the goals of the project, EWS-FLI1 drives the expression of CHEK1 and five other ATR pathway members. The loss of expression is not due to transcriptional repression and instead caused by degradation coupled with suppression of protein translation. The profound synergy is realized in vivo with a novel optimized schedule of this combination in subsets of ES models leading to durable complete responses in 50% of animals bearing two different ES xenografts. Conclusions: These data exploit EWS-FLI1 driven alterations in cell context to broaden the therapeutic window of berzosertib and cisplatin to establish a promising combination therapy and a novel in vivo schedule.

Published in

Cell Context Is the Third Axis of Synergy for the Combination of ATR Inhibition and Cisplatin in Ewing Sarcoma

Jess J, Sorensen KM, Boguslawski EA et al. · Clinical cancer research : an official journal of the American Association for Cancer Research 2024 · PMID 38506712 · doi:10.1158/1078-0432.CCR-23-3063

This dataset

Open GSE260602 in finder → Find more human ChIP / ATAC / CUT&Tag datasets → Ewing sarcoma landscape →

Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓

2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE260602_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓

3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: Look for peak files (.bed, .narrowPeak) and signal tracks (.bigWig) among the supplementary files; the raw reads are on ENA.

Also filed as BioProject PRJNA1082313 and SRA study SRP492627. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 38506712) ↗

Samples in this study

The sample list for this study is not cached yet. Press Load samples and it will be fetched from NCBI.

+ 2 more — browse all 2 samples with per-sample file links →

More Ewing sarcoma datasets

GSE332586 Mevalonate pathway activation in Ewing sarcoma reveals a 3D-specific synergy between statins and BCL-xL inhibition 36 samples same disease briefing · shares inhibition, synergy, sarcoma, ewing
GSE311851 LSD1 Performs Demethylase-Independent and Context-Specific Roles in Ewing Sarcoma 114 samples same disease briefing · shares context, sarcoma, ewing
GSE338238 Menin inhibition impairs metastatic colonization of Ewing sarcoma 48 samples same disease briefing · shares inhibition, sarcoma, ewing
GSE261693 TGFβ inhibition during radiation therapy enhances immune cell infiltration and decreases metastases in a novel humanized mouse model Ewing sarcoma. 3 samples same disease briefing · shares inhibition, sarcoma, ewing
GSE266666 Select chromatin complexes are essential drivers of pathogenic enhancer activity and gene expression in Ewing sarcoma [ChIP-Seq] 101 samples same disease briefing · shares sarcoma, ewing
GSE235218 Differential chromatin landscape in myxoid liposarcoma and Ewing sarcoma 6 samples same disease briefing · shares sarcoma, ewing
GSE267220 STAG2 loss in Ewing sarcoma alters enhancer-promoter contacts dependent and independent of EWS::FLI1 4 samples same disease briefing · shares sarcoma, ewing
GSE155456 HDGF ChIP-Seq in Ewing sarcoma cell line RD-ES 1 samples same disease briefing · shares sarcoma, ewing

Search all human ChIP / ATAC / CUT&Tag datasets in GEO →

Share this dataset

Metadata from NCBI GEO, cached and refreshed periodically — the NCBI page above is authoritative. Downloads link straight to NCBI/ENA; nothing is proxied through BioTransfer.