EWS/FLI confers tumor cell synthetic lethality to CDK12 inhibition in Ewing sarcoma

Many cancer types are driven by oncogenic transcription factors that act by inducing aberrant gene expression programs. Unfortunately, transcription factors have been notoriously difficult to drug. Alternative approaches would be to inhibit the aberrant transcriptional programs indirectly or to identify synthetic lethal dependencies in the context of the transcription factor abnormality. We screened THZ1, a recently reported CDK7/12/13 transcriptional inhibitor, in a cancer cell line collection to identify biomarkers of response. EWS/FLI-driven Ewing sarcoma cells were identified to be markedly sensitive to this compound. We determined that the primary target of THZ1 in Ewing sarcoma is CDK12 using genetic approaches and a new selective CDK12/13 inhibitor, THZ531. We performed global gene expression profiling to investigate the effects of THZ531 on transcriptional programs in Ewing sarcoma. We profiled two highly sensitive Ewing sarcoma cell lines A673 and TC32. Samples were treated in duplicate with DMSO or THZ531 at 100 nM or 500 nM for 6 hours.