CDK16 and CDK18 inhibition suppresses nuclear pore-mediated DNA repair and hepatocellular carcinoma

ABSTRACT: Inhibition of cyclin-dependent kinases (CDK) 4 and 6 has become part of the current standard-of-care treatment in advanced estrogen receptor-positive advanced 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 b-catenin driven hepatocellular carcinoma (HCC) is sensitive to the concomitant inactivation of CDK16 and 18. Whereas individual inactivation of CDK14-18 subfamily members displays little effect, concomitant genetic ablation of pharmacological inhibition of CDK16 and CDK18 results in proliferative arrest accompanied by DNA damage and apoptotic cell death. Mechanistically, these defects are associated to a novel role of these proteins in maintaining nuclear pore integrity and regulated 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 repair protein 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 b-catenin. Collectively, these data support the development of CDK16/18-targeted therapies for the treatment of HCC.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Marcos Malumbres  

LAB HEAD: Javier Muñoz Peralta

PROVIDER: PXD039769 | Pride | 2026-10-15

REPOSITORIES: Pride