{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["44(38)"],"submitter":["Olmedo-Pelayo J"],"pubmed_abstract":["Drug resistance is an ill-defined cause of dismal outcomes in cancer. Ewing sarcoma (EwS), a pediatric cancer characterized by high therapy failure rates, is driven by a single oncogenic event generating EWSR1::ETS gene fusions (primarily EWSR1::FLI1) in a silent genomic background. This provides a straightforward model to study the impact of gene fusions on drug responses. Here, we describe a novel mechanism of sensitivity to DNA topoisomerase 1 poisons in EwS. We discovered that EWS::FLI1 prevents the resolution of R-loops induced by these drugs via sequestering DHX9 helicase, ultimately resulting in R-loop accumulation, replication stress, and genome instability. In turn, excessive DHX9 or reduced EWS::FLI1 levels render EwS cells resistant to the active metabolite of irinotecan (SN-38)"],"journal":["Oncogene"],"pagination":["3537-3552"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12436182"],"repository":["biostudies-literature"],"pubmed_title":["EWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism."],"pmcid":["PMC12436182"],"pubmed_authors":["Garcia-Dominguez DJ","de Alava E","Ehlers AC","Carcaboso AM","Ohmura S","Delgado-Bellido D","Alonso J","Grunewald TGP","Granado-Calle E","Mackintosh C","Llombart-Bosch A","Scotlandi K","Machado I","Lobo-Selma L","Gomez-Herreros F","Jordan-Perez C","Monteiro-Amaral AT","Olmedo-Pelayo J"],"additional_accession":[]},"is_claimable":false,"name":"EWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism.","description":"Drug resistance is an ill-defined cause of dismal outcomes in cancer. Ewing sarcoma (EwS), a pediatric cancer characterized by high therapy failure rates, is driven by a single oncogenic event generating EWSR1::ETS gene fusions (primarily EWSR1::FLI1) in a silent genomic background. This provides a straightforward model to study the impact of gene fusions on drug responses. Here, we describe a novel mechanism of sensitivity to DNA topoisomerase 1 poisons in EwS. We discovered that EWS::FLI1 prevents the resolution of R-loops induced by these drugs via sequestering DHX9 helicase, ultimately resulting in R-loop accumulation, replication stress, and genome instability. In turn, excessive DHX9 or reduced EWS::FLI1 levels render EwS cells resistant to the active metabolite of irinotecan (SN-38)","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Oct","modification":"2026-06-03T02:58:20.126Z","creation":"2026-04-23T03:13:59.894Z"},"accession":"S-EPMC12436182","cross_references":{"pubmed":["40721661"],"doi":["10.1038/s41388-025-03496-9"]}}