What question did this study set out to answer?

To investigate how lurbinectedin affects EWS::FLI1 binding to chromatin and its impact on transcription in Ewing sarcoma.

April 5, 2026

Abstract 4776: Lurbinectedin alters EWS::FLI1 binding to chromatin to poison transcription

Key Points

To investigate how lurbinectedin affects EWS::FLI1 binding to chromatin and its impact on transcription in Ewing sarcoma.
Used confocal microscopy to observe EWS::FLI1 trafficking
Employed CUT&Tag and qPCR to study chromatin binding and transcription
Applied Bru-seq for evaluating nascent transcription
Conducted proximity ligation mass spectrometry for mechanistic insights
Silenced MAPK pathway members using siRNA to analyze relocalization effects
Lurbinectedin exposure results in EWS::FLI1 relocalization to the nucleolus
Transcription initiation and elongation of target genes are suppressed
Effects are dose and time dependent
Alterations in transcription are more significant for longer genes compared to shorter ones

Abstract

Abstract Relapsed Ewing sarcoma has dismal outcomes and has had minimal treatment advancements in the last 30 years - there is a critical need for the development of new treatments. The tumor is uniquely dependent on the oncogenic EWS::FLI1 fusion transcription factor to develop and maintain malignancy. Lurbinectedin is a small molecule analog of the natural product trabectedin that has shown efficacy in multiple cancers including Ewing sarcoma. The mechanism of toxicity of lurbinectedin in Ewing sarcoma is under investigation. Lurbinectedin exposure alters EWS::FLI1 trafficking into the nucleolus as measured by confocal microscopy. The subsequent impact of drug exposure on EWS::FLI1 binding to chromatin was determined by CUT Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4776.

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