Discovery in Hepatocellular Carcinoma Research

A study led by the Cell Cycle and Cancer Group at the Vall d’Hebron Institute of Oncology (VHIO) has identified a previously unknown vulnerability in liver cancer cells, offering a potential pathway for new therapies. The research, published in the journal Proceedings of the National Academy of Sciences (PNAS), focuses on hepatocellular carcinoma, the most common form of primary liver cancer in adults. The study shows that tumour cells rely on two proteins, CDK16 and CDK18, to repair DNA and continue multiplying. When both proteins are deactivated simultaneously, the cells accumulate irreparable genetic damage and die. This dual dependency had gone undetected in previous single-gene studies due to the proteins’ ability to compensate for each other.

How the Proteins Support Tumour Survival

CDK16 and CDK18 are cyclin-dependent kinases that regulate the transport of molecules between the cell nucleus and cytoplasm via nuclear pores. These ‘gateways’ help ensure that DNA repair proteins are correctly positioned within the nucleus. The research team found that disrupting both proteins impairs this transport, preventing effective DNA repair and ultimately halting tumour growth. In preclinical models, genetic inactivation of both proteins stopped the progression of established liver tumours in mice and led to their regression, supporting the idea that dual inhibition could be a viable therapeutic strategy.

To develop new therapies, we need to understand what allows a tumour cell to stay alive despite the damage it accumulates. 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.

, Dr Marcos Malumbres, ICREA Professor and Head of VHIO’s Cell Cycle and Cancer Group

Implications for Future Cancer Treatments

The finding challenges conventional approaches that assess gene function individually, highlighting the importance of studying compensatory mechanisms in cancer cells. Dr Malumbres stressed that this hidden dependency could exist in other cancers, urging further investigation. The research has received funding through the 2026 CaixaImpulse call from the ”la Caixa” Foundation for health innovation, which supports the development of pharmacological inhibitors targeting this mechanism. While no such drugs are yet available for clinical use, the results lay the groundwork for future drug development.

The goal now is to transform this vulnerability into a pharmacological strategy and determine which tumors could benefit most. The results offer a basis for progress, but we need to develop better inhibitors and evaluate their efficacy and safety before considering clinical application.

, Dr Marcos Malumbres

Sources: Vall d'Hebron - News, vallhebron.com, vhio.net.