Pipeline to evaluate YAP-TEAD inhibitors indicates TEAD inhibition represses NF2-mutant mesothelioma

Our plain-English summary of Pipeline to evaluate YAP-TEAD inhibitors indicates TEAD inhibition represses NF2-mutant mesothelioma, by R. Cunningham, S. Jia, K. Purohit, et al (Life Science Alliance, 2025).

The study

• Authors: R. Cunningham, S. Jia, K. Purohit, M.N. Fairley, M.K. Maniak, Y. Lin, N.S. Hui, R.E. Graham, A.G. Rossi, J. Cholewa-Waclaw, P.O. Bagnaninchi, N.O. Carragher, C.G. Hansen
• Journal: Life Science Alliance
• Published: 2025;8(10)
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

As the core, tumorigenic downstream effectors of the Hippo signalling pathway, YAP/TAZ and the TEAD family of transcription factors represent attractive targets for drug discovery efforts within cancer research. This is particularly true in the context of pleural mesothelioma, in which there are many recent preclinical developments and clinical trials evaluating the efficacy of TEAD inhibitors. The range of inhibitors has shown great promise, but comparisons of their performances are so far limited. Here, we develop a high-content pipeline that enables a comparative analysis of currently developed YAP/TAZ-TEAD inhibitors. We take advantage of isogenic cellular models that enable us to examine inhibitor specificity. We identify genetic compensation of the Hippo pathway transcriptional module, with implications for therapeutic targeting, and implement Cell Painting to develop a detailed morphological profiling pipeline that enables further characterisation, quantification, and analysis of off-target effects. Our pipeline is scalable and allows us to establish specificity and comparative potency within cancer-relevant assays in a clinically relevant cellular model of pleural mesothelioma.

© 2025 Cunningham et al.

In plain English

This was a laboratory study in cultured human cells, not a study of people exposed to asbestos; pleural mesothelioma was described in the introduction as an asbestos-induced cancer. The authors built a testing pipeline using non-malignant MeT-5A mesothelial cells carrying CRISPR/Cas9 knockouts of NF2, YAP or individual TEAD genes, plus HEK293A reporter cells, and compared three selective TEAD inhibitors (VT-107, K-975, IK-930) with dasatinib, verteporfin and lovastatin. At 1 micromolar for 24 hours, all compounds except lovastatin reduced TEAD luciferase activity, while IK-930 and lovastatin did not reduce YAP/TAZ signature gene expression in MeT-5A cells. Selective TEAD inhibitors had little effect on two-dimensional growth, whereas the non-selective inhibitors stopped growth above 1 micromolar even in YAP knockout cells. NF2-knockout spheroids grew larger and were more sensitive to most treatments. Loss of TEAD4 raised TEAD1 protein levels. Cell Painting showed broad, YAP-independent morphological changes with dasatinib and lovastatin. The authors concluded that direct TEAD inhibition appeared more specific than targeting the upstream kinase module.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: in vitro cell-culture drug-comparison study using isogenic CRISPR/Cas9 knockout cell lines, high-content imaging and Cell Painting morphological profiling
• Who was studied: Human cell lines: non-malignant MeT-5A mesothelial cells (wild type and CRISPR/Cas9 knockouts of NF2, YAP, TEAD1, TEAD4 and combinations, plus YAP-5SA expressing cells) and HEK293A cells (including TEAD knockout and LATS1/2 double knockout); laboratory work in Edinburgh, UK
• Exposure: 24-hour treatment with the selective TEAD inhibitors VT-107, K-975 and IK-930, compared with the non-selective YAP inhibitors verteporfin, lovastatin and dasatinib
• Main results:
  • In HEK293A cells, 24-hour treatment at 1 micromolar reduced TEAD luciferase activity with all tested compounds except lovastatin, with dasatinib giving the largest reduction
  • In MeT-5A cells, most inhibitors at 1 micromolar lowered YAP/TAZ signature gene expression, but IK-930 and lovastatin did not
  • In WT MeT-5A cells, dasatinib was the only tested inhibitor inducing YAP phosphorylation at low concentration; this response was reduced in NF2 knockout cells
  • In 72-hour 2D proliferation assays, selective TEAD inhibitors had little effect, whereas non-selective YAP inhibitors stopped growth above 1 micromolar; YAP knockout cells showed similar sensitivity to WT, indicating YAP-independent loss of viability
  • Spheroids: NF2 knockout spheroids were larger and YAP knockout spheroids smaller than WT; WT spheroids were significantly reduced only by VT-107 and K-975 at 10 micromolar, while NF2 knockout spheroids were more sensitive to nearly all treatments
  • Knockout of TEAD4 was associated with a consistent increase in TEAD1 protein levels, described by the authors as genetic compensation
  • Cell Painting morphological profiling showed features consistently disrupted independently of YAP by dasatinib and lovastatin, with fewer such off-target effects for verteporfin and the selective TEAD inhibitors
• The authors' conclusion: The authors concluded that their pipeline provides a framework for quantifying the efficacy and specificity of YAP/TAZ-TEAD inhibition in mesothelioma, and that their observations predict direct TEAD inhibition to be more specific, and likely more effective, than targeting the upstream kinase module
• Limitations the authors state:
  • TAZ dynamics were not studied; YAP alone was used as the readout of activity
  • Only TEAD isoforms with available antibodies and robust expression in MeT-5A cells were knocked out and examined
  • The authors state that 2D cellular models may be insufficient for evaluating these inhibitors, as mechanosensory conditions do not reflect real tissues

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Discovery, Pleural Mesothelioma, Clinical Trial.

Related studies

• Targeting YAP in malignant pleural mesothelioma — W.Q. Zhang, Y.Y. Dai, et al. (2017)
• Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling — J. Wu, A.M. Minikes, et al. (2019)
• Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers — E.A. Chapeau, L. Sansregret, et al. (2024)
• TEAD inhibitor induced switch in energy metabolism drives human podocyte injury in vitro — A. Zielinski, J. Hauptstein, et al. (2026)
• YAP/TAZ activation predicts clinical outcomes in mesothelioma and is conserved in in vitro model of driver mutations — R. Cunningham, S. Jia, et al. (2023)
• The YAP1 Signaling Inhibitors, Verteporfin and CA3, Suppress the Mesothelioma Cancer Stem Cell Phenotype — S. Kandasamy, G. Adhikary, et al. (2020)

Browse return to medical research.