Functional redundancy between atypical CDKs reveals a vulnerability in hepatocellular carcinoma
Year: 2026
Type: article
Abstract: The atypical cyclin-dependent kinase subfamily (CDK14–18) encompasses five related proteins with unclear function, and for which individual depletion has not demonstrated sustained therapeutic relevance. We report here that CDK16 and CDK18 compensate each other and liver cancer cells are sensitive to the concomitant inactivation of both kinases, resulting in persistent defects in DNA repair and subsequent cell death. These effects are linked to a role of CDK16/18 in regulating nucleocytoplasmatic transport through phosphorylation of nuclear pore complex components, including NUP35. Genetic ablation of Cdk16 and Cdk18 in established liver tumors driven by MYC and beta-catenin oncogenes triggers DNA damage in cancer cells without affecting adjacent normal tissue, ultimately leading to tumor regression. Collectively, these findings provide a rationale for the development of CDK16–18 inhibitors—likely targeting multiple subfamily members due to their structural similarity—as a strategy against aggressive cancers, such as hepatocellular carcinoma, where effective treatment options remain limited.
Authors: Diego Martínez-Alonso, Enrique Nogueira, Luis R. López-Sainz, Alexis P. Pérez, Carolina Villarroya-Beltri, Alejandro Garcia-Diaz, Gloria C. Bonel-Pérez, Aicha El Bakkali, Senn Wakahashi, Agustín Sánchez-Belmonte, Isabel García-Cao, Jesus Castillo-Sanchez, José González-Martínez, Diego Megias, Jana Sánchez, Stephan Geley, Javier Muñoz, Sagrario Ortega, Fleur M. Ferguson, Nathanael S. Gray, David J. Shields, Amaia Lujambio, Guillermo de Cárcer, Marcos Malumbres
Institutions: Spanish National Cancer Research Centre, Centro de Investigación del Cáncer, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Cáncer, Vall d'Hebron Institute of Oncology, Kobe University, University of California San Diego, Stanford University, Pfizer (United States), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Institució Catalana de Recerca i Estudis Avançats
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7224088136