YAP/TAZ-TEAD signalling axis: A new therapeutic target in malignant pleural mesothelioma

Our plain-English summary of YAP/TAZ-TEAD signalling axis: A new therapeutic target in malignant pleural mesothelioma, by K.A. Papavassiliou, A.A. Sofianidi, A.G. Papavassiliou (Journal of Cellular and Molecular Medicine, 2024).

The study

• Authors: K.A. Papavassiliou, A.A. Sofianidi, A.G. Papavassiliou
• Journal: Journal of Cellular and Molecular Medicine
• Published: 2024;28(8):e18330
• Type of article: Review
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The Hippo signalling pathway, a highly conserved signalling cassette, regulates organ size by controlling cell growth, apoptosis and stem cell self-renewal. The tumourigenic potential of this pathway is largely attributed to the activity of YAP/TAZ, which activate the TEAD1-4 transcription factors, leading to the expression of genes involved in cell proliferation and suppression of cell death. Aberrant regulation of the YAP/TAZ-TEAD signalling axis is commonly observed in malignant pleural mesothelioma (MPM), an insidious neoplasm of the pleural tissue that lines the chest cavity and covers the lungs with poor prognosis. Given the limited effectiveness of current treatments, targeting the YAP/TAZ-TEAD signalling cascade has emerged as a promising therapeutic strategy in MPM. Several inhibitors of the YAP/TAZ-TEAD signalling axis are presently undergoing clinical development, with the goal of advancing them to clinical use in the near future.

© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

In plain English

This article was a review, not a new study; the authors stated that no new data were generated. It described how two proteins, YAP and TAZ, work with TEAD proteins to switch on genes for cell growth and the suppression of cell death. The authors called malignant pleural mesothelioma (MPM) an aggressive asbestos-associated tumour and cited earlier work reporting NF2 inactivation in 30%–40% of cases. They summarised drugs aimed at this pathway. For VT3989, they cited a phase I trial in 67 patients who had progressed on prior chemotherapy, 29 with MPM. The drug was reported safe and well tolerated, and seven patients, six with refractory malignant mesothelioma (pleural or non-pleural), had partial responses. Other drugs were in ongoing phase I trials or had been tested only in laboratory and animal models. One of these, K-975, was associated with renal (kidney) toxicity. The authors concluded that allosteric inhibitors that disrupt the YAP–TEAD interaction had shown promising antitumour effects, mainly in preclinical studies, and that ongoing trials would show how effective these inhibitors are in MPM. They cautioned that YAP/TAZ may also suppress tumours in some contexts.

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: Review of published laboratory, animal and early clinical trial reports on drugs targeting the YAP/TAZ-TEAD signalling pathway in malignant pleural mesothelioma; no new data
• Who was studied: No study population of its own. The review summarised other researchers' reports, including a phase I trial of VT3989 in 67 patients (29 with MPM).
• Exposure: Asbestos exposure was not studied. The review describes MPM as an asbestos-associated tumour. The subject is drugs that block the YAP/TAZ-TEAD pathway: ION537, VT3989, IK-930, IAG933, SWTX-143, K-975 and JM7.
• Main results:
  • Citing earlier work, the authors reported that NF2 inactivation occurs in 30%–40% of MPM cases.
  • Citing a first-in-human phase I trial of VT3989 (reported by other researchers), the authors stated that it enrolled 67 patients who had progressed on prior chemotherapy, 29 of whom had MPM, and that the drug was found to be safe and well tolerated.
  • In that VT3989 trial, the most common adverse events were proteinuria, albuminuria and peripheral edema. The review's table lists 7 grade 3 treatment-related adverse events and 1 grade 4 event (cardiomyopathy).
  • In the VT3989 trial, seven patients achieved partial responses, six of them with refractory malignant mesothelioma (pleural or non-pleural). The table gives a clinical benefit response rate of 57% in malignant mesothelioma patients, defined as partial response plus stable disease for more than 8 weeks.
  • ION537, IK-930 and IAG933 were listed as being in ongoing phase I clinical trials. No efficacy results from these trials were given.
  • K-975 showed antitumour activity in preclinical mesothelioma models but was associated with renal toxicity, which the authors said might present challenges in clinical use.
• The authors' conclusion: The authors concluded that allosteric inhibitors that disrupt the YAP–TEAD interaction had shown promising antitumour efficacy, mainly in the preclinical setting, and that ongoing clinical trials will show how effective these inhibitors are in managing MPM.
• Limitations the authors state:
  • The authors cautioned that YAP/TAZ may also have a tumour-suppressive role depending on context, so targeting this pathway in future trials needs careful consideration.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Apoptosis, STEM, Neoplasm, Prognosis.

Related studies

• 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)
• Dropwort-induced metabolic reprogramming restrains YAP/TAZ/TEAD oncogenic axis in mesothelioma — C. Pulito, E. Korita, et al. (2019)
• Pan-cancer analyses of bromodomain containing 9 as a novel therapeutic target reveals its diagnostic, prognostic potential and biological mechanism in human tumours — Y. Chen, Z. Gao, et al. (2024)
• Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling — J. Wu, A.M. Minikes, et al. (2019)
• Pipeline to evaluate YAP-TEAD inhibitors indicates TEAD inhibition represses NF2-mutant mesothelioma — R. Cunningham, S. Jia, et al. (2025)
• NF2/Merlin Inactivation and Potential Therapeutic Targets in Mesothelioma — T. Sato, Y. Sekido (2018)

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