Authors
James H McGinnis, Shuai Wang, Ryan A O'Hara, Xin Zhao, Purbita Saha, Xin Bai, Danielle Sherry, Jiwoong Kim, Alberto Bremauntz Enriquez, Jacinth Naidoo, Florentina Vandiver, Hanspeter Niederstrasser, Shuguang Wei, Prema L Mallipeddi, Yang Xie, Lianbo Li, Cynthia J Meyer, Jessica A Kilgore, Altair L Dube, Kenneth D Westover, Bruce A Posner, Noelle S Williams, Joseph M Ready, Laura A Banaszynski, David G McFadden
Published in
Cancer discovery. Jul 14, 2026. Epub Jul 14, 2026.
Abstract
Ewing sarcoma is characterized by a chromosomal translocation resulting in the fusion protein EWSR1::FLI1. We utilize endogenous EWSR1::FLI1 target gene reporters in patient-derived cell lines to perform a high-throughput phenotypic screen to identify small molecules that impair the EWSR1::FLI1 transcriptional program. We discovered that inhibitors of cyclin-dependent kinase 8 (CDK8), including a novel pyridyl imidazole, altered transcription of EWSR1::FLI1 target genes and CDK8 co-localized with EWSR1::FLI1 preferentially on single GGAA DNA binding motifs. Using pooled CRISPR screening, biochemical studies, and chromatin profiling, we discovered that CDK8 inhibitors suppressed proliferation of Ewing sarcoma cells through a gain-of-function mechanism by inducing molecular trapping of the CDK8 kinase module and Mediator complex on chromatin. This mechanism has implications for the development of small molecules to target transcription and suggests that impairment of transcriptional regulatory complex dynamics might serve as a vulnerability in cancers in which the dominant oncogenes act as dosage-sensitive transcription factors.
PMID:
42447057
Bibliographic data and abstract were imported from PubMed on 15 Jul 2026.
Read full publication at:
Please sign in
to see all details.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 8
- Comments 0