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EWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism

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...

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Main Authors: Olmedo-Pelayo, Joaquin (Author) , Granado-Calle, Esperanza (Author) , Delgado-Bellido, Daniel (Author) , Lobo-Selma, Laura (Author) , Jordan-Perez, Carmen (Author) , Monteiro-Amaral, Ana T. (Author) , Ehlers, Anna (Author) , Ohmura, Shunya (Author) , Garcia-Dominguez, Daniel J. (Author) , Mackintosh, Carlos (Author) , Carcaboso, Angel M. (Author) , Alonso, Javier (Author) , Machado, Isidro (Author) , Llombart-Bosch, Antonio (Author) , Scotlandi, Katia (Author) , Grünewald, Thomas G. P. (Author) , Gomez-Herreros, Fernando (Author) , de Alava, Enrique (Author)
Format: Article (Journal)
Language:English
Published: 07 October 2025
In: Oncogene
Year: 2025, Volume: 44, Issue: 38, Pages: 3537-3552
ISSN:1476-5594
DOI:10.1038/s41388-025-03496-9
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41388-025-03496-9
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41388-025-03496-9
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Author Notes:Joaquin Olmedo-Pelayo, Esperanza Granado-Calle, Daniel Delgado-Bellido, Laura Lobo-Selma, Carmen Jordan-Perez, Ana T. Monteiro-Amaral, Anna C. Ehlers, Shunya Ohmura, Daniel J. Garcia-Dominguez, Carlos Mackintosh, Angel M. Carcaboso, Javier Alonso, Isidro Machado, Antonio Llombart-Bosch, Katia Scotlandi, Thomas G.P. Grünewald, Fernando Gomez-Herreros and Enrique de Alava
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Summary: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) independent of proliferation and global transcription rates. This resistance helps explain how elevated DHX9 levels predict worse clinical outcomes. Overall, our research demonstrates the impact of a dominant mutation on cancer drug sensitivity, highlighting its significant clinical implications.
Item Description:Online verfügbar: 28. Juli 2025
Gesehen am 16.12.2025
Physical Description:Online Resource
ISSN:1476-5594
DOI:10.1038/s41388-025-03496-9

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