Mediator kinases as therapeutic targets in Colorectal cancer

• Applicant: Dr. Marius Volker Dannappel
• Subject Area: Cell Biology ; General Genetics and Functional Genome Biology
• Term: from 2018 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 404188400

Colorectal cancer (CRC) is the third most common cancer worldwide and fourth most common cause of cancer related death. Germline or somatic mutations in the Wnt/β-catenin pathway resulting in dysregulated β-catenin-activity can be found in more than 90 percent of colorectal cancers. Despite effort, no the Wnt/β-catenin inhibitors are available for CRC treatment. Cyclin dependent kinase 8 (CDK8) was identified as a transducer of β-catenin-signals and other oncogenic pathways to regulate gene expression as part of the multi-meric protein complex, the Mediator. CDK19 is a paralog of CDK8 and its functions remain largely unknown. A recent study suggests that pharmacological inhibition of CDK8/19 could be a promising strategy to inhibit β-catenin signalling during CRC therapy. Here, I propose to study the function of Mediator kinases for intestinal homeostasis and colon cancer in vivo using mouse models with individual or combined deletion of CDK8 and CDK19. In parallel, I will use ex vivo human patient derived colorectal cancer organoids to test the hypothesis that CDK8/19 inhibition can prevent β-catenin-driven tumour growth and thus, could be employed as a therapeutic target. In conclusion, this project will elucidate the function of mediator kinases in vivo and assess their potential as targets for CRC treatment.

• DFG Programme: Research Fellowships
• International Connection: Australia
• Host: Professor Dr. Ron Firestein