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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| Hauptverfasser: | , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
07 October 2025
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| In: |
Oncogene
Year: 2025, Jahrgang: 44, Heft: 38, Pages: 3537-3552 |
| ISSN: | 1476-5594 |
| DOI: | 10.1038/s41388-025-03496-9 |
| Online-Zugang: | 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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| Verfasserangaben: | 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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| 245 | 1 | 0 | |a EWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism |c 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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| 520 | |a 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. | ||
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