Functional redundancy between atypical CDKs reveals a vulnerability in hepatocellular carcinoma
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
- José González‐Martínez (ORCID: https://orcid.org/0000-0002-3850-6803)
- Senn Wakahashi (ORCID: https://orcid.org/0000-0001-9197-1790)
- Guillermo de Cárcer (ORCID: https://orcid.org/0000-0002-3220-1785)
- Marcos Malumbres (ORCID: https://orcid.org/0000-0002-0829-6315)
- David J. Shields (ORCID: https://orcid.org/0009-0003-5238-3912)
- Isabel Garcı́a-Cao (ORCID: https://orcid.org/0000-0002-4582-0403)
- Carolina Villarroya‐Beltri (ORCID: https://orcid.org/0000-0003-2284-4020)
- Diego Martínez‐Alonso (ORCID: https://orcid.org/0000-0003-0521-5134)
- Nathanael S. Gray (ORCID: https://orcid.org/0000-0001-5354-7403)
- Gloria C. Bonel-Pérez (ORCID: https://orcid.org/0000-0001-6546-3039)
- Fleur M. Ferguson (ORCID: https://orcid.org/0000-0003-4091-7617)
- Enrique Nogueira (ORCID: https://orcid.org/0000-0002-4222-928X)
- Agustín Sánchez-Belmonte (ORCID: https://orcid.org/0000-0001-6936-1873)
- Sagrario Ortega (ORCID: https://orcid.org/0000-0002-1865-7102)
- Alexis P. Pérez (ORCID: https://orcid.org/0000-0002-5238-5294)
- Javier Muñoz (ORCID: https://orcid.org/0000-0003-3288-3496)
- Luis Rodrigo López-Sainz
- Alejandro Garcia-Diaz (ORCID: https://orcid.org/0009-0003-6818-1450)
- Diego Megı́as (ORCID: https://orcid.org/0000-0003-0755-0518)
- Stephan Geley (ORCID: https://orcid.org/0000-0002-3169-5322)
- Amaia Lujambio (ORCID: https://orcid.org/0000-0002-2798-1481)
- Aicha El Bakkali (ORCID: https://orcid.org/0000-0001-9261-8761)
- Jesus Castillo-Sanchez (ORCID: https://orcid.org/0009-0008-7011-2020)
- Jana Sánchez
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Pfizer (United States) (US)
- Instituto de Salud Carlos III (ES)
- University of California San Diego (US)
- Spanish National Cancer Research Centre (ES)
- Centro de Investigación del Cáncer (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Vall d'Hebron Institute of Oncology (ES)
- Tisch Cancer Institute (US)
- Kobe University (JP)
- Stanford University (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-10-28
- DOI
- https://doi.org/10.1073/pnas.2529474123
- Primary Topic
- Cancer-related Molecular Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- “la Caixa” Foundation
- Comunidad de Madrid