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<p>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 <i>EWSR1</i>::<i>ETS</i> gene fusions (primarily <i>EWSR1::FLI1</i>) 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月28日

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  • 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,
  • Enrique de Alava

摘要

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.