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Human malignant mesothelioma NCI-H226 cells treated with TEAD inhibitor K-975 in SCID mice.

ABSTRACT: We investigate the dependence of human malignant mesothelioma on functional TEAD transcription factors to maintain fully established tumors in vivo. We show that TEAD inhibitor K-975 stops tumor growth in vivo, eventually causing tumor regression, by downregulating TEAD activity and altering, thus, TEAD-dependent transcription in a dysfunctional Hippo genetic background. Our data validate the concept of inhibiting an activated YAP1/TEAD complex for the treatment of malignant pleural mesothelioma patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196726 | GEO | 2022/02/17

REPOSITORIES: GEO

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Human malignant mesothelioma NCI-H226 cells treated with TEAD inhibitor K-975 in SCID mice.

Project description:Human malignant mesothelioma NCI-H226 cells treated with TEAD inhibitor K-975 in SCID mice.

| PRJNA806971 | ENA

Conditional expression of sh-YAP1 modulates YAP1/TEAD-dependent transcription and causes regression of established human malignant mesothelioma MSTO-211H [sh-YAP1] xenografts.

Project description:We investigate the dependence of human malignant pleural mesothelioma on a functional YAP1-TEAD transcription factor complex to maintain fully established tumors in vivo. We show that, in a dysfunctional Hippo genetic background, downregulation of YAP1 by shRNA results in modulation of YAP1/TEAD-dependent gene expression and regression of established tumor xenografts. Our data demonstrate that, in the context of a mutated Hippo pathway, YAP1 activity is essential to maintain the growth of mesothelioma cells in vivo, thus validating the concept of inhibiting the activated YAP1/TEAD complex for the treatment of malignant pleural mesothelioma patients.

2022-02-17 | GSE196672 | GEO

Conditional expression of a dominant negative-TEAD2 construct modulates YAP1/TEAD-dependent transcription and arrests growth of human malignant mesothelioma MSTO-211H [TEAD2-dn] xenografts.

Project description:We investigate the dependence of human malignant pleural mesothelioma on a functional YAP1-TEAD transcription factor complex to maintain fully established tumors in vivo. We show that, in a dysfunctional Hippo genetic background, expression of a dominant negative TEAD2 modulates YAP1/TEAD-dependent gene expression and inhibits growth of established tumor xenografts. Our data demonstrate that, in the context of a mutated Hippo pathway, TEAD2 activity is essential to maintain the growth of mesothelioma tumors in vivo, thus validating the concept of inhibiting the activated YAP1/TEAD complex for the treatment of malignant pleural mesothelioma patients.

2022-02-17 | GSE196691 | GEO

Pharmacodynamics of malignant mesothelioma MSTO-211H dn-TEAD2 xenograft recurrence.

Project description:We investigate the dependence of human malignant pleural mesothelioma on a functional YAP1-TEAD transcription factor complex to maintain fully established tumors in vivo. We show that, in a dysfunctional Hippo genetic background, expression of a doxycycline-dependent dominant negative TEAD2 temporarily modulates YAP1/TEAD-dependent gene expression and inhibits growth of established tumor xenografts. Recovery of tumor growth is associated with TEAD-dependent transcription comparable to untreated tumors, therefore, re-activation of TEAD transcription complexes.

2022-02-17 | GSE196714 | GEO

Next Generation Sequencing Quantitative Analysis of TEAD Inhibitors in NCI-H226 cells

Project description:Purpose: The goal of this study is to understand the signaling pathway alteration in NCI-H226 cells treated with TEAD inhibitors. Methods: Mesothelioma cell line NCI-H226 was chosen to be treated with TEAD inhibitors at 1μM for 24 hours. Total RNA was isolated for the analysis. RNA samples were sent to Novogen for library construction, RNA sequencing and raw data process. Conclusions: Our study privides gene expression profiling evidence to validate TEAD inhibitors to block TEAD transcriptional activity in mesothelioma cells.

2022-10-15 | GSE215114 | GEO

Next Generation Sequencing Quantitative Analysis of TEAD Palmitoylation Inhibitor TM2 in NCI-H226 cells

Project description:Purpose: The goal of this study is to understand the signaling pathway alteration in NCI-H226 cells treated with new TEAD autopalmitoylation inhibitor TM2, and to further validate TEAD inhibitor for specifity in TEAD-YAP interuption. Methods: Mesothelioma cell line NCI-H226 was chosen to be treated with TEAD palmitoylation inhibitor TM2 at 1μM for 24 hours. Total RNA was isolated for the analysis. RNA samples were sent to Novogen for library construction, RNA sequencing and raw data process. Conclusions: Our study privides gene expression profiling evidence to validate our TEAD palmitoylation inhibitor TM2 as specific small molecule to block TEAD transcriptional activity in mesothelioma cells.

2024-05-01 | GSE203421 | GEO

Correlative analysis from a phase I clinical trial of intrapleural administration of oncolytic vaccinia virus (Olvi-vec) in patients with malignant pleural mesothelioma

Project description:Regional delivery of oncolytic viruses has been shown to promote immune responses. Malignant pleural effusions comprise an immunosuppressive microenvironment, and the ability of oncolytic viruses to generate immune responses following regional delivery in patients with malignant pleural effusions is unknown. We conducted a phase I clinical trial that studied the intrapleural administration of oncolytic vaccinia virus to establish the safety and feasibility in patients with malignant pleural effusion due to malignant pleural mesothelioma or metastatic disease. In patients with malignant pleural mesothelioma, by correlative analysis of pre- and post-treatment tumor biopsies, we provide insight into tumor-specific viral uptake and associated immune responses.

2023-01-27 | GSE223395 | GEO

Mesothelioma differential expression

Project description:To investigate the molecular events controlling malignant transformation of human pleural cells, we compared constitutive gene expression of mesothelioma cells to that of pleural cells. Using cDNA microarray and high-density filter array, we assessed expression levels of > 6500 genes. Most of the highly expressed transcripts were common to both cell lines and included genes associated with stress response and DNA repair, outcomes consistent with the radio- and chemo-resistance of mesothelioma. Interestingly, of the fewer than 300 genes that differed between cell lines, most functioned in (i) macromolecule stability, (ii) cell adhesion and recognition, (iii) cell migration (invasiveness), and (iv) extended cell division Keywords: c-DNA array from Incyte Pharmaceuticals™, cell line comparison

2006-02-16 | GSE4241 | GEO

A novel irreversible TEAD inhibitor, SWTX-143, blocks the Hippo pathway and causes tumor regression in preclinical mesothelioma models [SubQ]

Project description: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 partner transcription factors, the TEAD1-4 factors, are therefore promising anti-cancer targets. Due to 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 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 human subcutaneous xenograft models 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 exquisite sensitivity of mesothelioma 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 great potential to treat multiple Hippo-mutant solid tumor types.

2023-10-04 | GSE222962 | GEO

A novel irreversible TEAD inhibitor, SWTX-143, blocks the Hippo pathway and causes tumor regression in preclinical mesothelioma models [Invitro]

2023-10-04 | GSE222960 | GEO