Targeting Mediator kinase CDK8 and CDK19 in normal and cancer states
CDK8 and its paralog CDK19 (collectively known as Mediator kinase) transduce b-catenin and other transcriptional programmes as part of a multi-meric transcriptional complex called Mediator
Targeting Mediator kinase will provide therapeutic benefit for colon cancer and other Wnt driven malignancies. Specific aims of this project will use sophisticated mouse models and genetically engineered cell lines to:
1) To characterise the function of Mediator kinase components Cdk8 and Cdk19 in normal tissue homeostasis and intestinal tumourigenesis in vivo. Using inducible and conditional Mediator kinase genetically engineered knockout mice, we will characterise the contribution of Mediator kinase function in normal intestinal homeostasis and malignancy.
2) To investigate Mediator kinase inhibition in clinically relevant colon cancer models. We will utilise both genetic and pharmacological CDK8/19 inhibitors to examine the consequences of Mediator kinase loss in clinically meaningful cancer models (cell lines, organoids and patient-derived xenografts).
3) To identify and characterise CDK8/19 kinase substrates that mediate its oncogenic activity. Using innovative proteomic approaches coupled with powerful genetic and chemical reagents, we will identify and characterise CDK8/19 kinase targets in b-catenin driven malignancy.