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CDK 7/9 inhibition amplifies mithramycin's suppression of Ewing sarcoma cell proliferation

Ewing sarcoma is driven by the fusion of the EWSR1 and FLI1 genes generated by a t(11:22) chromosomal translocation. Ewing sarcoma cells depend on the EWS‐FLI1 fusion product, a constitutively active oncogenic transcription factor, and become nonviable when EWS‐FLI1 driven transcription is inhibited. Mithramycin, a natural antineoplastic compound, has been identified as a potent EWS‐FLI1 inhibitor and is highly toxic to Ewing sarcoma cells. However, clinical trials of mithramycin in patients with Ewing sarcoma have been limited due to toxicity. To overcome this challenge, we sought to identify genes that sensitize Ewing sarcoma cells to mithramycin when inhibited. We identified RNA pol II inhibition as a potent sensitizer to mithramycin and phenocopied this with the dual cyclin dependent kinase (CDK) 7/9 inhibitors PHA‐767491 and SNS‐032. We show a marked suppression of cellular proliferation in response to mithramycin in combination with either CDK 7/9 inhibitor at concentrations significantly lower than mithramycin alone.