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

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)

SUBMITTER: Olmedo-Pelayo J 

PROVIDER: S-EPMC12436182 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature