Understanding the anti-cancer effects of new YAP/TAZ inhibitors to treat malignant mesothelioma

Asbestos exposure causes malignant mesothelioma, for which there are no effective therapies available. The most frequent driver mutations of
mesothelioma are mutations in the Hippo pathway that cause the hyperactivation of its downstream effectors, the transcriptional co-activators
YAP and TAZ. Therefore, the Hippo pathway, and in particular the activity of YAP/TAZ, is one of the most promising targets to develop novel targeted
therapies against mesothelioma. We have recently developed small molecule inhibitors that potently inhibit YAP/TAZ activity and that suppress
the growth of mesothelioma cells in culture and cause the regression of mesothelioma tumors in mice without causing overt toxicity. We now
propose to determine the molecular mechanisms by which these compounds modulate YAP/TAZ activity and to identify the mesothelioma
patient population that would benefit from these inhibitors. Addressing these questions is important because this will further direct the clinical
development of YAP/TEAD inhibitors for mesothelioma therapy.