A vulnerability in tumor cells’ nuclear gateways could pave the way for new treatments

• A VHIO-led study identifies a vulnerability in liver cancer: CDK16 and CDK18 compensate for each other, but their simultaneous inactivation causes persistent DNA damage and tumour cell death.
• These proteins regulate transport between the nucleus and the cytoplasm through nuclear pores, gateways whose function helps tumour cells repair their genetic material.
• In preclinical models, genetic inactivation of both proteins halted growth and induced the regression of established liver tumours in mice, supporting the development of inhibitors as a potential therapeutic strategy.
• The findings, published in PNAS, open an avenue for developing new therapies and reveal a dependency that may go unnoticed in studies that analyse genes one at a time.

A study led by the Cell Cycle and Cancer Group at the Vall d’Hebron Institute of Oncology (VHIO) has identified a vulnerability in liver cancer that could guide the development of new therapies. The work, published in Proceedings of the National Academy of Sciences (PNAS), shows that some tumour cells depend on the combined action of two proteins, CDK16 and CDK18, to repair their DNA and continue multiplying. When both are inactivated, damage accumulates and the cells’ ability to survive is impaired.

The research, led by Dr Marcos Malumbres, ICREA Professor, Head of VHIO’s Cell Cycle and Cancer Group and Director of its Systems Oncology Programme, focuses on hepatocellular carcinoma, the most common type of primary liver cancer in adults.

“Although treatments are available that can control the disease and prolong survival, advanced forms remain particularly challenging. Identifying new dependencies in tumour cells allows us to explore treatments that target mechanisms different from those addressed by current therapies,” says Malumbres.

“To develop new therapies, we need to understand what allows a tumour cell to stay alive despite the damage it accumulates,” the researcher continues. “In this work, we have identified two proteins that support each other. By eliminating both, we deprive the tumour of an important means of repairing its genetic material.”

An escape route that concealed the vulnerability

Cyclin-dependent kinases (CDKs) are a family of proteins that regulate various cellular activities. Some members of this family are known for their role in tumour cell division, to the extent that inhibitors of two family members, CDK4 and CDK6, are part of the standard treatment for advanced hormone receptor-positive breast cancer. However, the functions of other family members, such as CDK16 and CDK18, were unknown.

The team observed that eliminating just one of these proteins generally had limited effects on liver cancer cells. “This was explained by their ability to compensate for each other: when one was absent, the other could maintain functions necessary for cell survival. Inactivating both removed that protection and led to persistent defects in DNA repair,” explains Diego Martínez-Alonso, a postdoctoral researcher in VHIO’s Cell Cycle and Cancer Group and first author of the study.

The findings help explain why certain cancer vulnerabilities can go unnoticed. Many studies search for potential therapeutic targets by eliminating genes one at a time. However, this approach may fail to detect a dependency if another protein takes over the function of the eliminated gene.

“If we study these proteins separately, we may conclude that they have little therapeutic relevance,” says Malumbres. “Analysing them together reveals a dependency that was hidden. This is a very important concept in cancer therapy and encourages us to look for other vulnerabilities concealed by compensatory mechanisms that protect tumour cells.”

Access to the nucleus, a weak point in liver cancer

The research also explains part of the mechanism underlying this dependency. DNA is in the cell nucleus, surrounded by an envelope that regulates the exchange of molecules with the rest of the cell. This exchange takes place through structures called nuclear pores, which act as gateways.

The researchers discovered that CDK16 and CDK18 modify components of these pores. These modifications help DNA repair proteins accumulate appropriately in the nucleus and at sites where genetic material needs to be repaired.

When CDK16 and CDK18 are eliminated, this process is disrupted. Tumour cells accumulate lesions that they cannot resolve effectively, stop proliferating and may die. The study thus links the function of the nuclear gateways to a capability essential for cancer survival: keeping its DNA repairable.

From a therapeutic perspective, this connection offers an opportunity. Interfering with the mechanisms that allow tumours to tolerate genetic damage could turn a requirement of cancer cells into their weak point.

“The aim now is to translate this vulnerability into a pharmacological strategy and determine which tumours could benefit most,” concludes Malumbres. “The results provide a basis for moving forward, but we need to develop better inhibitors and evaluate their efficacy and safety before considering clinical application.”

This idea recently received funding through the 2026 CaixaImpulse call from the “la Caixa” Foundation for health innovation projects.

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Reference

Diego Martínez-Alonso, Enrique Nogueira, Luis R. López-Sainz, Alexis P. Pérez, Carolina Villarroya-Beltri, Alejandro García, 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, and Marcos Malumbres. Functional redundancy between atypical CDKs reveals a vulnerability in hepatocellular carcinoma. PNAS, October 28, 2026, 123 (44) e2529474123. https://doi.org/10.1073/pnas.2529474123

About VHIO

The Vall d’Hebron Institute of Oncology (VHIO), established in 2006 and located within the Vall d’Hebron Campus, is a reference comprehensive cancer center for personalized medicine in oncology. Through our purely translational and multidisciplinary research model, we aim to improve the prevention, early diagnosis and treatment of cancer by transforming the latest scientific discoveries made in the laboratory into early phase clinical trials for the development of more effective therapies to improve the quality of life and survival  of cancer patients.

VHIO forms part of the CERCA – Research Centres of Catalonia system and is accredited as a Severo Ochoa Center of Excellence.

Research at VHIO would not be possible without the support received from our patrons –Generalitat de Catalunya, Fundació Privada CELLEX, "La Caixa" Foundation, Fundación FERO, Fundación BBVA and the CRIS Cancer Foundation– and the public funding it receives as well as the generous support from institutional supporters, private institutions, companies, associations, societies, and individual donors. Only with such continued support will VHIO continue to advance personalized and targeted therapies against cancer.