CDK16 and CDK18 inhibition suppresses nuclear pore-mediated DNA repair and hepatocellular carcinoma [liver tumor]

However, many tumor types are resistant to current CDK inhibitors and the therapeutic value of other CDK family members remains to be validated. By using gene-editing techniques in human cancer cells and genetically-modified mouse models we report here that MYC and beta-catenin driven hepatocellular carcinoma (HCC) is sensitive to the inactivation of CDK16 and CDK18.

Whereas individual ablation of CDK14-18 subfamily members displays little effect, concomitant genetic ablation or pharmacological inhibition of CDK16 and CDK18 results in proliferative arrest accompanied by DNA damage and apoptotic cell death. Mechanistically, these defects are associated with a novel role of these proteins in maintaining nuclear pore integrity and the regulation of nucleocytoplasmatic transport. Cyclin Y-CDK16/18 complexes directly phosphorylate the nuclear pore complex (NPC) components NUP35 and NUP214.