Confirmation of cdk8/19 inhibitor selectivity and activity in colorectal cancer

The Mediator complex is an evolutionarily conserved regulator of gene expression, influencing chromatin structure and RNA polymerase II-mediated transcription. Its activity is modulated by a protein kinase module, which includes cyclin-dependent kinases 8 and 19, that phosphorylate RNA polymerase II and transcription factors to regulate gene expression. CDK8 exhibits both oncogenic and tumour-suppressive activities depending on the cellular context, while the contributions of CDK19 remain less well understood. Based on prior data with our CDK8/19 inhibitor - 3,4,5-trisubstituted pyridine compound CCT251545 - we selected the human colorectal cancer cell line COLO205 for profiling experiments. This model is highly dependent on mutant BRAF and oncogenic β-catenin-driven WNT signaling and exhibits high basal β-catenin-dependent TCF/LEF promoter activity, which is sensitive to CDK8/19 inhibition in vitro and in vivo.