Journal Article

DKFZ-2025-01559

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png EWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism.

Olmedo-Pelayo, J. ; Granado-Calle, E. ; Delgado-Bellido, D. ; Lobo-Selma, L. ; Jordan-Perez, C. ; Monteiro-Amaral, A. T. ; Ehlers, A. C.DKFZ* ; Ohmura, S.DKFZ* ; Garcia-Dominguez, D. J. ; Mackintosh, C. ; Carcaboso, A. M. ; Alonso, J. ; Machado, I. ; Llombart-Bosch, A. ; Scotlandi, K. ; Grünewald, T.DKFZ* ; Gomez-Herreros, F. ; de Alava, E.

2025
Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41388-025-03496-9

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) 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.

Note: 2025 Oct;44(38):3537-3552

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Contributing Institute(s):

1. Translationale Pädiatrische Sarkomforschung (B410)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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