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000303208 1001_ $$00000-0003-2768-971X$$aOlmedo-Pelayo, Joaquin$$b0
000303208 245__ $$aEWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism.
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000303208 520__ $$aDrug resistance is an ill-defined cause of dismal outcomes in cancer. Ewing sarcoma (EwS), a pediatric cancer characterized by high therapy failure rates, is driven by a single oncogenic event generating EWSR1::ETS gene fusions (primarily EWSR1::FLI1) in a silent genomic background. This provides a straightforward model to study the impact of gene fusions on drug responses. Here, we describe a novel mechanism of sensitivity to DNA topoisomerase 1 poisons in EwS. We discovered that EWS::FLI1 prevents the resolution of R-loops induced by these drugs via sequestering DHX9 helicase, ultimately resulting in R-loop accumulation, replication stress, and genome instability. In turn, excessive DHX9 or reduced EWS::FLI1 levels render EwS cells resistant to the active metabolite of irinotecan (SN-38) independent of proliferation and global transcription rates. This resistance helps explain how elevated DHX9 levels predict worse clinical outcomes. Overall, our research demonstrates the impact of a dominant mutation on cancer drug sensitivity, highlighting its significant clinical implications.
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000303208 7001_ $$aGranado-Calle, Esperanza$$b1
000303208 7001_ $$00000-0002-9588-4747$$aDelgado-Bellido, Daniel$$b2
000303208 7001_ $$aLobo-Selma, Laura$$b3
000303208 7001_ $$aJordan-Perez, Carmen$$b4
000303208 7001_ $$aMonteiro-Amaral, Ana T$$b5
000303208 7001_ $$0P:(DE-He78)9b3d0cef2b1553fc9d2c5f24d91c12e1$$aEhlers, Anna C$$b6$$udkfz
000303208 7001_ $$0P:(DE-He78)c25b54b0c834093d1f884d2615e305d6$$aOhmura, Shunya$$b7$$udkfz
000303208 7001_ $$00000-0001-8150-2747$$aGarcia-Dominguez, Daniel J$$b8
000303208 7001_ $$aMackintosh, Carlos$$b9
000303208 7001_ $$00000-0002-8485-426X$$aCarcaboso, Angel M$$b10
000303208 7001_ $$00000-0002-6287-8391$$aAlonso, Javier$$b11
000303208 7001_ $$00000-0001-7318-1330$$aMachado, Isidro$$b12
000303208 7001_ $$aLlombart-Bosch, Antonio$$b13
000303208 7001_ $$00000-0001-6114-9499$$aScotlandi, Katia$$b14
000303208 7001_ $$0P:(DE-He78)7a590ab95c6f7ba52880452da78ecd6c$$aGrünewald, Thomas$$b15$$udkfz
000303208 7001_ $$00000-0002-5693-3489$$aGomez-Herreros, Fernando$$b16
000303208 7001_ $$00000-0001-8400-046X$$ade Alava, Enrique$$b17
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