A Novel Irreversible TEAD Inhibitor, SWTX-143, Blocks Hippo Pathway Transcriptional Output and Causes Tumor Regression in Preclinical Mesothelioma Models.

Autor:	Hillen H; VIB Center for Cancer Biology and KU Leuven Department of Oncology, KU Leuven, Leuven, Belgium., Candi A; Cistim Leuven vzw, Leuven, Belgium., Vanderhoydonck B; Cistim Leuven vzw, Leuven, Belgium., Kowalczyk W; VIB Center for Cancer Biology and KU Leuven Department of Oncology, KU Leuven, Leuven, Belgium., Sansores-Garcia L; VIB Center for Cancer Biology and KU Leuven Department of Oncology, KU Leuven, Leuven, Belgium., Kesikiadou EC; VIB Center for Cancer Biology and KU Leuven Department of Oncology, KU Leuven, Leuven, Belgium., Van Huffel L; VIB Center for Cancer Biology and KU Leuven Department of Oncology, KU Leuven, Leuven, Belgium., Spiessens L; VIB Center for Cancer Biology and KU Leuven Department of Oncology, KU Leuven, Leuven, Belgium., Nijs M; Cistim Leuven vzw, Leuven, Belgium., Soons E; Cistim Leuven vzw, Leuven, Belgium., Haeck W; Cistim Leuven vzw, Leuven, Belgium., Klaassen H; Cistim Leuven vzw, Leuven, Belgium., Smets W; Cistim Leuven vzw, Leuven, Belgium., Spieser SA; Cistim Leuven vzw, Leuven, Belgium., Marchand A; Cistim Leuven vzw, Leuven, Belgium., Chaltin P; Cistim Leuven vzw, Leuven, Belgium.; Center for Drug Design and Discovery (CD3), KU Leuven, Leuven, Belgium., Ciesielski F; NovAliX, Strasbourg, France., Debaene F; NovAliX, Strasbourg, France., Chen L; SpringWorks Therapeutics, Stamford, Connecticut., Kamal A; SpringWorks Therapeutics, Stamford, Connecticut., Gwaltney SL; SpringWorks Therapeutics, Stamford, Connecticut., Versele M; Cistim Leuven vzw, Leuven, Belgium., Halder GA; VIB Center for Cancer Biology and KU Leuven Department of Oncology, KU Leuven, Leuven, Belgium.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2024 Jan 03; Vol. 23 (1), pp. 3-13.
DOI:	10.1158/1535-7163.MCT-22-0681
Abstrakt:	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. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
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