Matt Shair

“Targeting Mediator Kinases as a Therapeutic Strategy for Cancer”

CDK8 and CDK19 are kinases that associate with the Mediator co-activator complex which regulates aspects of transcription. I will describe our findings that cortistatin A is a potent and highly selective inhibitor of CDK8 and CDK19 in cells and that inhibition of these kinases is a new therapeutic approach to acute myeloid leukemia (AML) including in two in vivo mouse models of AML. Inhibition of CDK8 and CDK19 in AML cells had highly specific effects on gene expression in AML cells, contrary to the widespread role of Mediator in transcription. Further, we have found that cortistatin A upregulates a small set of cell identity genes in AML cells which may play a key role in the sensitivity of these tumors to CDK8/CDK19 inhibition. Activation of cell identity genes may be a general means of suppressing tumor cell growth.