The kinase inhibitor GNF-7 is synthetically lethal in topoisomerase 1 deficient Ewing Sarcoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1271555 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Relapsed Ewing sarcoma is treated with TOP1 inhibitors. Our study confirmed prior studies showing that downregulation of TOP1 is a mechanism of resistance to camptothecin. We then screened a large library of clinically relevant compounds and found that TOP1-deficient Ewing sarcoma cells are more sensitive to the kinase inhibitor GNF-7. RNA-seq results reveal that GNF-7 modulates EWS/FLI1 gene signatures in both TOP1 wild type and TOP1-deficient cells.
2025-08-20 | GSE298880 | GEO
Project description:SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells
| PRJNA628515 | ENA
Project description:This SuperSeries is composed of the following subset Series: GSE36857: Goldengate Methylation analysis: Ewing Sarcoma GSE36858: 5- AZA treatment of EWS cell lines Refer to individual Series
2012-09-01 | E-GEOD-36859 | biostudies-arrayexpress
Project description:SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells II
| PRJNA628517 | ENA
Project description:SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells I
| PRJNA479751 | ENA
Project description:The cellular origin of Ewing tumor (ET), a tumor of bone or soft tissues characterized by specific fusions between EWS and ETS genes, is highly debated. Through gene expression analysis comparing ETs with a variety of normal tissues, we show that the profiles of different EWS-FLI1-silenced Ewing cell lines converge toward that of mesenchymal stem cells (MSC). Moreover, upon EWS-FLI1 silencing, two different Ewing cell lines can differentiate along the adipogenic lineage when incubated in appropriate differentiation cocktails. In addition, Ewing cells can also differentiate along the osteogenic lineage upon long-term inhibition of EWS-FLI1. These in silico and experimental data strongly suggest that the inhibition of EWS-FLI1 may allow Ewing cells to recover the phenotype of their MSC progenitor. Experiment Overall Design: Ewing tumors and EWS-FLI-1 inhibited cell lines were profiled on Affymetrix U133A (GPL96) arrays.
2008-06-15 | E-GEOD-7007 | biostudies-arrayexpress
Project description:Ewing Sarcoma (EwS) is a rare pediatric malignancy characterized by a unique t(11:22) (q24;q12) translocation resulting in the EWSR1::FLI1 fusion. Recent reports indicate the EWSR1::FLI1 fusion onco-protein drives aberrant expression of numerous transcripts, including Lipoxygenase Homology Domains 1 (LOX¬HD1). Given its highly restricted protein expression pattern and role in EwS tumorigenesis and metastasis, LOXHD1 may serve as a novel immunotherapeutic target in this malignancy. LOXHD1 immunogenic epitopes restricted to HLA-A*02:01 allowed for the isolation of high avidity TCRs. LOXHD1-specific TCR engineered CD8+ T cells confer cytotoxic activity against a panel of HLA-A*02:01+ EwS tumor cell lines and adoptive transfer leads to tumor eradication in a mouse xenograft model of EwS. This study nominates LOXHD1 as an onco-fusion regulated / non-mutated EwS tumor associated antigen with expression limited to inner hair cells of the cochlea, adult testis, and EwS
2025-05-06 | PXD046803 | Pride
Project description:Oncoproteins such as the BRAFV600E kinase entrust cancer cells with malignant properties, but they also create unique vulnerabilies. Therapeutic targeting of the BRAFV600E-driven cytoplasmic signaling network has proven ineffective, since patients regularly relapse with reactivation of the targeted signaling pathways. Here, we identified the nuclear protein SFPQ to be synthetically lethal with BRAFV600E in a loss-of-function shRNA screen. SFPQ depletion decreased proliferation and induced apoptosis in BRAFV600E-driven colorectal and melanoma cells, and reduced tumor growth in xenografts. Mechanistically, SFPQ loss in BRAF-mutant cancer cells triggered the Chk1-dependent replication checkpoint, resulting in replication stress in the absence of overt DNA damage. Affected cells stalled in S-Phase with hallmark signs of impaired replication factories. Induction of BRAFV600E and concomitant loss of SFPQ sensitized cells to a combination of DNA replication checkpoint inhibitors and chemically induced replication stress, pointing towards future therapeutic approaches exploiting nuclear vulnerabilities induced by BRAFV600E.
2020-04-27 | GSE149370 | GEO
Project description:Oncoproteins such as the BRAFV600E kinase entrust cancer cells with malignant properties, but they also create unique vulnerabilies. Therapeutic targeting of the BRAFV600E-driven cytoplasmic signaling network has proven ineffective, since patients regularly relapse with reactivation of the targeted signaling pathways. Here, we identified the nuclear protein SFPQ to be synthetically lethal with BRAFV600E in a loss-of-function shRNA screen. SFPQ depletion decreased proliferation and induced apoptosis in BRAFV600E-driven colorectal and melanoma cells, and reduced tumor growth in xenografts. Mechanistically, SFPQ loss in BRAF-mutant cancer cells triggered the Chk1-dependent replication checkpoint, resulting in replication stress in the absence of overt DNA damage. Affected cells stalled in S-Phase with hallmark signs of impaired replication factories. Induction of BRAFV600E and concomitant loss of SFPQ sensitized cells to a combination of DNA replication checkpoint inhibitors and chemically induced replication stress, pointing towards future therapeutic approaches exploiting nuclear vulnerabilities induced by BRAFV600E.
2019-12-31 | GSE116631 | GEO
Project description:Ewing sarcoma is an aggressive pediatric small round cell tumor that predominantly occurs in bone. Approximately 85% of Ewing sarcomas harbor the EWS/FLI fusion protein, which arises from a chromosomal translocation, t(11:22)(q24:q12). EWS/FLI interacts with numerous lineage-essential transcription factors to maintain mesenchymal progenitors in an undifferentiated state. We previously showed that EWS/FLI binds the osteogenic transcription factor RUNX2 and prevents osteoblast differentiation. In this study, we investigated the role of another Runt-domain protein, RUNX3, in Ewing sarcoma. RUNX3 participates in mesenchymal-derived bone formation and is a context dependent tumor suppressor and oncogene. RUNX3 was detected in all Ewing sarcoma cells examined, whereas RUNX2 was detected in only 73% of specimens. Like RUNX2, RUNX3 binds to EWS/FLI via its Runt domain. EWS/FLI prevented RUNX3 from activating the transcription of a RUNX-responsive reporter, p6OSE2. Stable suppression of RUNX3 expression in the Ewing sarcoma cell line A673 delayed colony growth in anchorage independent soft agar assays and reversed expression of EWS/FLI-responsive genes. These results demonstrate an important role for RUNX3 in Ewing sarcoma. RNA-seq to compare transcriptiome of control A673 ewing sarcoma cells stably expression a non-target or RUNX3 shRNA
2014-05-01 | E-GEOD-56900 | biostudies-arrayexpress