Peer-reviewedCC BY-NC-ND 4.0Proceedings of the National Academy of Sciences of the United States of America
Functional redundancy between atypical CDKs reveals a vulnerability in hepatocellular carcinoma
16 affiliations
- 1Cell Division and Cancer group, Molecular Oncology program, Spanish National Cancer Research Center, Madrid 28029, Spain
- 2Cancer Cell Cycle group, Systems Oncology program, Vall d’Hebron Institute of Oncology, Barcelona 08035, Spain
- 3Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III, Madrid 28029, Spain
- 4Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
- 5Confocal Microscopy Unit, Biotechnology program, Spanish National Cancer Research Center, Madrid 28029, Spain
- 6Proteomics Unit, Biotechnology program, Spanish National Cancer Research Center, Madrid 28029, Spain
- 7Division of Molecular Pathophysiology, Medical University, Innsbruck 6020, Austria
- 8Mouse Gene Editing Unit, Biotechnology program, Spanish National Cancer Research Center, Madrid 28029, Spain
- 9Department of Biochemistry and Molecular Biophysics, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California in San Diego, La Jolla, CA 92093-0657
- 10Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305
- 11Pfizer Centers for Therapeutic Innovation, Pfizer Inc.,, New York, NY 10016
- 12Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- 13Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- 14The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029
- 15Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY 10029
- 16Institut Català de Recerca i Estudis Avançats, Barcelona 08010, Spain
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.
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BibTeX
@article{martinezalonso2026functional,
title = {{Functional redundancy between atypical CDKs reveals a vulnerability in hepatocellular carcinoma}},
author = {Diego Martínez-Alonso and Enrique Nogueira and Luis R. López-Sainz and Alexis P. Pérez and Carolina Villarroya-Beltri and Alejandro Garcia-Diaz and Gloria C. Bonel-Pérez and Aicha El Bakkali and Senn Wakahashi and Agustín Sánchez-Belmonte and Isabel García-Cao and Jesus Castillo-Sanchez and José González-Martínez and Diego Megias and Jana Sánchez and Stephan Geley and Javier Muñoz and Sagrario Ortega and Fleur M. Ferguson and Nathanael S. Gray and David J. Shields and Amaia Lujambio and Guillermo de Cárcer and Marcos Malumbres},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2529474123},
url = {https://doi.org/10.1073/pnas.2529474123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Functional redundancy between atypical CDKs reveals a vulnerability in hepatocellular carcinoma
AU - Diego Martínez-Alonso
AU - Enrique Nogueira
AU - Luis R. López-Sainz
AU - Alexis P. Pérez
AU - Carolina Villarroya-Beltri
AU - Alejandro Garcia-Diaz
AU - Gloria C. Bonel-Pérez
AU - Aicha El Bakkali
AU - Senn Wakahashi
AU - Agustín Sánchez-Belmonte
AU - Isabel García-Cao
AU - Jesus Castillo-Sanchez
AU - José González-Martínez
AU - Diego Megias
AU - Jana Sánchez
AU - Stephan Geley
AU - Javier Muñoz
AU - Sagrario Ortega
AU - Fleur M. Ferguson
AU - Nathanael S. Gray
AU - David J. Shields
AU - Amaia Lujambio
AU - Guillermo de Cárcer
AU - Marcos Malumbres
PY - 2026
DA - 2026/10/28
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2529474123
UR - https://doi.org/10.1073/pnas.2529474123
AB - 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.
SN - 0027-8424
SN - 1091-6490
ER -