It’s a Trap! CDK8 Inhibition Reveals a Shared Vulnerability through Mediator Trapping in Fusion-Driven Pediatric Sarcomas

A large proportion of pediatric sarcomas are driven by neomorphic transcription factors that are challenging therapeutic targets. In this issue, two independent studies identify CDK8 as a shared therapeutic vulnerability in pediatric fusion oncoprotein-driven sarcomas and reveal that CDK8 inhibitors disrupt oncogenic transcriptional programs through an unexpected gain-of-function mechanism involving Mediator complex trapping on chromatin. See related article by Zhang et al., p. 2344 See related article by McGinnis et al., p. 2366.