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CDK8 Inhibition Induces Mediator Trapping and Impairment of the EWSR1::FLI1 Transcriptional Program in Ewing Sarcoma.
Cancer Discovery · · Journal Article
McGinnis, Wang + more
Abstract ↗AI summary
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CDK8 inhibitors, including a novel pyridyl imidazole, impair the EWSR1::FLI1 transcriptional program in Ewing sarcoma cells by inducing Mediator trapping on chromatin.
- Why it matters: Ewing sarcoma depends on the dosage-sensitive EWSR1::FLI1 transcriptional program, but vulnerabilities that disrupt its regulatory complex dynamics are not well defined.
- What they did: Using endogenous EWSR1::FLI1 target gene reporters in patient-derived cell lines, the team ran a high-throughput phenotypic screen, then combined pooled CRISPR, biochemical assays, and chromatin profiling.
- The result: CDK8 inhibition suppresses Ewing sarcoma proliferation via a gain-of-function mechanism that traps the CDK8 kinase module and Mediator on chromatin, linked to CDK8 co-localization at single GGAA motifs.
The findingWhy it mattersWhat they didThe result
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