Targeting the Hippo Pathway Is a New Potential Therapeutic Modality for Malignant Mesothelioma

Our plain-English summary of Targeting the Hippo Pathway Is a New Potential Therapeutic Modality for Malignant Mesothelioma, by Y. Sekido (Cancers, 2018).

The study

• Author: Y. Sekido
• Journal: Cancers
• Published: 2018;10(4)
• Type of article: Review
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) constitutes a very aggressive tumor that arises from the pleural or peritoneal cavities and is highly refractory to conventional therapies. Several key genetic alterations are associated with the development and progression of MM including mutations of the CDKN2A/ARF, NF2, and BAP1 tumor-suppressor genes. Notably, activating oncogene mutations are very rare; thus, it is difficult to develop effective inhibitors to treat MM. The NF2 gene encodes merlin, a protein that regulates multiple cell-signaling cascades including the Hippo pathway. MMs also exhibit inactivation of Hippo pathway components including LATS1/2, strongly suggesting that merlin-Hippo pathway dysregulation plays a key role in the development and progression of MM. Furthermore, Hippo pathway inactivation has been shown to result in constitutive activation of the YAP1/TAZ transcriptional coactivators, thereby conferring malignant phenotypes to mesothelial cells. Critical YAP1/TAZ target genes, including prooncogenic CCDN1 and CTGF, have also been shown to enhance the malignant phenotypes of MM cells. Together, these data indicate the Hippo pathway as a therapeutic target for the treatment of MM, and support the development of new strategies to effectively target the activation status of YAP1/TAZ as a promising therapeutic modality for this formidable disease.

In plain English

This article was a review by a single author of published research on the Hippo pathway, a cell-signaling pathway involved in restricting cell growth, in malignant mesothelioma. It reported no new patient data. The author noted that mesothelioma is most often caused by asbestos exposure, but the review dealt with tumor genetics and possible treatments, not with exposure. Citing earlier studies, the review reported three main findings. An estimated 40–50% of mesothelioma cases carry an inactivating change in the NF2 gene. LATS2 inactivation was found in seven of 20 mesothelioma cell lines and in 11% of 61 pleural mesothelioma primary cultures. Asbestos-exposed mice lacking one copy of Nf2 developed mesothelioma faster than asbestos-treated normal littermates. The review also described laboratory work in which verteporfin suppressed YAP1 activity in mesothelioma cell lines. The author concluded that the literature supports developing treatments based on Hippo pathway changes. The author also noted three cautions: very few studies had tested YAP1/TAZ inhibition, such treatments might cause serious side effects, and current staining tests of pathway status are neither very sensitive nor specific.

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: Narrative review of published laboratory, animal and clinical research (single author)
• Who was studied: No study population of its own; the review covered published research on malignant mesothelioma (pleural and peritoneal), including human tumor tissues, cell lines, mouse models and clinical trials
• Exposure: Not an exposure study. The review stated that asbestos is the most common cause of mesothelioma. No fiber types or doses were analyzed.
• Main results:
  • Citing earlier studies, the review stated that an estimated 40–50% of mesothelioma cases harbor an NF2-inactivating mutation or deletion
  • In cited studies, LATS2 inactivation was found in seven of 20 mesothelioma cell lines, and 11% of 61 malignant pleural mesothelioma primary cultures had LATS2-inactivating mutations or deletions
  • In a cited study, YAP1 expression was seen in more than 70% of the primary mesothelioma tissues analyzed
  • In cited mouse studies, asbestos-exposed Nf2 (+/−) knockout mice showed markedly accelerated mesothelioma formation compared with asbestos-treated wild-type littermates
  • In cited laboratory studies, verteporfin suppressed YAP1 activity and the viability, invasion and tumor sphere formation of mesothelioma cell lines in vitro
  • A cited phase-II trial of the FAK inhibitor defactinib (VS-6063) in mesothelioma was halted for lack of observed benefit
• The authors' conclusion: The author concluded that the literature supports developing a new treatment approach based on the Hippo pathway changes seen in mesothelioma cells, but that more studies are needed
• Limitations the authors state:
  • Very few studies had investigated YAP1/TAZ inhibition in mesothelioma, either in the laboratory or in animals
  • Targeting YAP1/TAZ might cause serious and unexpected adverse effects, because the Hippo pathway is essential to normal cell functions
  • Current staining methods and antibodies used to assess merlin and YAP1/TAZ status are neither very sensitive nor specific

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, CDKN2A, BAP1, Merlin, Mesothelial Cells.

Related studies

• Experimental assessment of computationally nominated small molecules targeting the YAP-TEAD interface in Hippo pathway-altered mesothelioma cell models — G.J. Weiss, J.C. Loftus, et al. (2026)
• Preventive and therapeutic opportunities: targeting BAP1 and/or HMGB1 pathways to diminish the burden of mesothelioma — M. Carbone, M. Minaai, et al. (2023)
• Genetic profiling and pathway analysis in bladder carcinoma: Implications for therapeutic targeting — S. Vasishta, U.S. Adiga, et al. (2025)
• Therapeutic potential of targeting S100A11 in malignant pleural mesothelioma — H. Sato, M. Sakaguchi, et al. (2018)
• Therapeutic Potential of Carica papaya (L.) Extract on NRF2/KEAP1 and Apoptotic Pathways in Asbestos-Induced Lung Toxicity — U. Haider, M. Ahmad, et al. (2026)
• TGF-β synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth — M. Fujii, T. Toyoda, et al. (2012)

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