CDK8 inhibition sequesters Med1 at EWS-FLI enhancers [RNA-Seq]

To identify small molecules that selectively impair the oncogenic transcriptional program enacted by EWS-FLI1 we employed a novel phenotypic screen. Our screening hits were enriched for inhibitors of cyclin dependent kinase 8/19.

Inhibition of CDK8/19 resulted in a proliferation defect in Ewing sarcoma cells and a reduction in growth of Ewing sarcoma xenografts. We performed a genome wide pooled CRISPR screen that suggested that small molecule inhibition of CDK8/19 acted in a gain-of-function manner that did not replicate the effects of CDK8/19 genetic knockout. Through biochemical studies and chromatin profiling, we discovered that CDK8/19 inhibitors act through a novel trapping mechanism in which the inhibitor prevents dissociation of the CDK8 kinase from core Mediator.