HKUMed uncovered the key mechanism of cancer drug resistance. The research was led by Professor Jeff Ti Shih-Chieh (middle).
A research team from the School of Biomedical Sciences at the LKS Faculty of Medicine, the University of Hong Kong (HKUMed), has uncovered the mechanism underlying how cancer patients respond to a widely used cancer drug, known as paclitaxel, offering insights that may help overcome cancer drug resistance. The study found that small differences in microtubules, the structures inside cells that help the cells divide and move, can determine the efficacy of paclitaxel. This finding was published in Nature Chemical Biology [link to the publication].
Paclitaxel is listed by the World Health Organization (WHO) as an essential medicine, and has long been used to treat breast, ovarian and lung cancers. However, not all tumours respond equally well to paclitaxel. Professor Jeff Ti Shih-Chieh, Assistant Professor, School of Biomedical Sciences, HKUMed, said, 'One suspected reason for this difference is the variation in tubulin, a protein that makes up microtubules and is the main target of paclitaxel. In particular, a specific form of tubulin, known as β3-tubulin, has been associated with resistance to paclitaxel, leading to poor treatment outcomes.'
There is an urgent need to understand the underlying mechanism of this resistance for developing new therapies that are more effective and have fewer side effects.
Variants in tubulin lead to paclitaxel resistance
The research team used a variety of advanced approaches to study how paclitaxel interacts with different human tubulin variants. By using state-of-the-art protein engineering, single-molecule fluorescence microscopy, near-atomic-resolution cryo-electron microscopy, and genome editing of cancer cells, the team found an internal communication network within tubulin that helps control its shape and behaviour. This internal network plays an important role in determining how effectively paclitaxel can bind to tubulin and prevent cancer cells from growing.
The study identified a specific site within the β3-tubulin protein that contributes to paclitaxel resistance. Even though this site does not directly interact with the drug, changing it alters the shape of tubulin within microtubules, allowing paclitaxel to bind and work more effectively. Further experiments in lung cancer cells confirmed that the identified site in β3-tubulin directly affects the effectiveness of paclitaxel.
Unlocking tubulin's internal network to boost cancer treatment
'Our study marks a significant step in understanding why some cancers do not respond well to paclitaxel, and how this resistance can arise from small structural differences in tubulin,' said Professor Ti. 'These insights will help us develop better microtubule-targeting therapies for various cancers and other tubulin-related diseases, such as neurodegeneration and infertility.'
Professor Ti emphasised the implications of this research for translational medicine. 'By uncovering an internal network within tubulin that shapes its properties and drug response, the study may have broader relevance beyond cancer treatment,' he said. 'For example, developing small molecules or antibodies that can modify the shape and activity of tubulin could provide innovative therapeutic strategies for tubulinopathies – diseases caused by mutations in specific tubulin variants.'
About the research team
The research project was led by Professor Jeff Ti Shih-Chieh, Assistant Professor, School of Biomedical Sciences, HKUMed. The lead author is a PhD candidate Luo Jingyi from the same School.
Acknowledgments
The study was funded by the General Research Fund and the Collaborative Research Fund from the Research Grants Council, the Government of the Hong Kong Special Administrative Region of the People's Republic of China; with cryo-electron microscopy data collection at the LKS Cryo-EM Laboratory, and single-molecule fluorescence microscopy performed at the Imaging and Flow Cytometry Core, Centre for PanorOmic Sciences, HKUMed.
