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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
Published on: September 13, 2018
A Novel Irreversible TEAD Inhibitor, SWTX-143, Blocks Hippo Pathway Transcriptional Output and Causes Tumor
Hanne Hillen1, Aurélie Candi2, Bart Vanderhoydonck2
1VIB Center for Cancer Biology and KU Leuven Department of Oncology, KU Leuven, Leuven, Belgium.
Abstract:
The Hippo pathway and its downstream effectors, the YAP and TAZ transcriptional coactivators, are deregulated in multiple different types of human cancer and are required for cancer cell phenotypes in vitro and in vivo, while largely dispensable for tissue homeostasis in adult mice. YAP/TAZ and their main partner transcription factors, the TEAD1-4 factors, are therefore promising anticancer targets. Because of frequent YAP/TAZ hyperactivation caused by mutations in the Hippo pathway components NF2 and LATS2, mesothelioma is one of the prime cancer types predicted to be responsive to YAP/TAZ-TEAD inhibitor treatment. Mesothelioma is a devastating disease for which currently no effective treatment options exist. Here, we describe a novel covalent YAP/TAZ-TEAD inhibitor, SWTX-143, that binds to the palmitoylation pocket of all four TEAD isoforms. SWTX-143 caused irreversible and specific inhibition of the transcriptional activity of YAP/TAZ-TEAD in Hippo-mutant tumor cell lines. More importantly, YAP/TAZ-TEAD inhibitor treatment caused strong mesothelioma regression in subcutaneous xenograft models with human cells and in an orthotopic mesothelioma mouse model. Finally, SWTX-143 also selectively impaired the growth of NF2-mutant kidney cancer cell lines, suggesting that the sensitivity of mesothelioma models to these YAP/TAZ-TEAD inhibitors can be extended to other tumor types with aberrations in Hippo signaling. In brief, we describe a novel and specific YAP/TAZ-TEAD inhibitor that has potential to treat multiple Hippo-mutant solid tumor types.
Insights
A new drug, SWTX-143, targets YAP/TAZ-TEAD interactions, showing promise for treating Hippo-mutant cancers like mesothelioma. This inhibitor effectively reduced mesothelioma tumors in preclinical models, offering hope for new cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The Hippo pathway, including YAP/TAZ coactivators and TEAD transcription factors, is crucial for cancer cell growth but dispensable for normal adult tissue.
- Dysregulation of the Hippo pathway, particularly mutations in NF2 and LATS2, leads to YAP/TAZ hyperactivation in various cancers, including mesothelioma.
- Mesothelioma is an aggressive cancer with limited treatment options, making YAP/TAZ-TEAD a promising therapeutic target.
Purpose of the Study:
- To develop and characterize a novel covalent inhibitor targeting the YAP/TAZ-TEAD transcriptional complex.
- To evaluate the efficacy of this inhibitor in preclinical models of mesothelioma and other Hippo-mutant cancers.
Main Methods:
- Development of a novel covalent YAP/TAZ-TEAD inhibitor, SWTX-143, designed to bind the TEAD palmitoylation pocket.
- Assessment of SWTX-143's inhibitory activity on YAP/TAZ-TEAD transcriptional activity in cancer cell lines.
- Evaluation of SWTX-143's therapeutic effect in subcutaneous and orthotopic mesothelioma xenograft models.
- Testing SWTX-143's efficacy in NF2-mutant kidney cancer cell lines.
Main Results:
- SWTX-143 demonstrated irreversible and specific inhibition of YAP/TAZ-TEAD transcriptional activity in Hippo-mutant cancer cells.
- Treatment with SWTX-143 led to significant regression of mesothelioma tumors in both subcutaneous and orthotopic mouse models.
- SWTX-143 selectively inhibited the growth of NF2-mutant kidney cancer cell lines, indicating broader applicability.
Conclusions:
- SWTX-143 is a novel, specific, and potent YAP/TAZ-TEAD inhibitor with significant preclinical anti-cancer activity.
- This inhibitor shows therapeutic potential for mesothelioma and other solid tumors with Hippo pathway aberrations.
- SWTX-143 represents a promising new therapeutic strategy for difficult-to-treat cancers.
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