The Hippo pathway regulates the YAP and TAZ transcriptional coactivators, which are often upregulated in human cancers. YAP/TAZ partner with TEAD transcription factors to drive cancer phenotypes. Because mutations in the Hippo pathway genes NF2 and LATS2 lead to YAP/TAZ hyperactivation, mesothelioma is a prime candidate for treatment with YAP/TAZ-TEAD inhibitors. Mesothelioma currently has no good treatment options.
The authors developed a new covalent YAP/TAZ-TEAD inhibitor called SWTX-143 that binds all TEAD isoforms and blocks YAP/TAZ-TEAD transcriptional activity. SWTX-143 caused strong tumor regression in mesothelioma mouse models, including a subcutaneous xenograft model and an orthotopic model.