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

Inhibition of cyclin-dependent kinases (CDK) 4 and 6 has become part of the current standard-of-care treatment in advanced estrogen receptor-positive breast cancer. 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. CDK16/18 inhibition leads to defective nuclear accumulation of the DNA recombinase RAD51, altering DNA repair and inducing lethal levels of DNA damage. Genetic ablation of Cdk16 and Cdk18 in vivo triggers DNA damage and apoptotic cell death in murine liver tumors induced by MYC and -catenin, resulting in tumor regression. Collectively, these data support the development of CDK16/18-targeted therapies for the treatment of HCC.