IRR Group leader Dr Hansen and colleagues have developed a new testing pipeline that can compare the performance of drugs for the aggressive cancer, pleural mesothelioma. This approach has the potential to help develop better treatments for this and other cancers. Pleural mesothelioma is an aggressive cancer of the lung’s lining, usually caused by asbestos. It is often diagnosed late, most patients only live 12-18 months after diagnosis, and no cure exists. This makes the search for targeted, effective treatments urgent.The Hippo signalling pathway is a cellular control system that helps regulate cell growth and division. This pathway is disrupted in cancers such as pleural mesothelioma, which causes two proteins - YAP and TAZ – to become overactive. These two proteins then team up with TEAD proteins to drive cancer growth. Our scalable, adaptable pipeline has the potential to accelerate mesothelioma drug development and advance therapies for other cancers driven by the same signalling pathway. Richard Cunningham IRR researcher and paper’s first author Drugs that block this YAP/TAZ-TEAD activity are showing promising results, with some already in early clinical trials. Comparing their strengths, weaknesses, and side effects however, has been challenging.IRR researchers, together with the Anne Rowling Regenerative Neurology Clinic and the Institute of Genetics and Cancer, have created a high-tech testing system to compare both direct and indirect YAP/TAZ-TEAD inhibitors side by side. Using specially designed cell models of mesothelioma, they examined how specific each drug is for inhibiting YAP/TAZ-TEAD activity, and what unintended changes the drugs might cause to cell structure and behaviour. Microscopy images comparing the effect of two drugs on cancer cell shape and behaviour. Direct TEAD-inhibitors (VT-107) causes reduced YAP activity inside the cell nucleus (magenta), with minimal impact on cell shape (green), compared to non-specific YAP-inhibitors (dasatinib), which alters both. They also used an advanced imaging technique called ‘Cell Painting’ to capture changes in cell structure and detect off-target effects with high resolution caused by treatment. Finally, they developed functional assays that could measure how well different drugs block YAP/TAZ–TEAD’s ability to drive cancer growth. This study provides a platform for refining therapeutic strategies targeting the Hippo pathway. It will enable future drug targeting evaluation, with direct translational potential in mesothelioma treatment. Dr Carsten Hansen IRR Group Leader The findings reveal that 3D cell models give a more realistic view than traditional 2D systems and show that directly targeting and blocking TEAD is more effective than aiming for the upstream, indirect targets of YAP or TAZ. The team also uncovered ‘compensatory’ effects, where blocking one type of TEAD protein prompts cancer cells to rely on another – which is important for future drug design.This approach is designed to be scalable and adaptable for cancer research. The scientists say their system could not only speed up mesothelioma drug development but also improve therapies for other cancers driven by the same pathway.This work was funded by the Worldwide Cancer Research and Chief Scientist Office (CSO)-LifeArc.Read the full article in Life Science AllianceHansen research group Tags CIR Publication date 12 Aug, 2025
