NF2/Merlin Inactivation and Potential Therapeutic Targets in Mesothelioma

Our plain-English summary of NF2/Merlin Inactivation and Potential Therapeutic Targets in Mesothelioma, by T. Sato, Y. Sekido (International Journal of Molecular Sciences, 2018).

The study

• Authors: T. Sato, Y. Sekido
• Journal: International Journal of Molecular Sciences
• Published: 2018;19(4)
• Type of article: Review
• Cited by: 91 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The neurofibromatosis type 2 (NF2) gene encodes merlin, a tumor suppressor protein frequently inactivated in schwannoma, meningioma, and malignant mesothelioma (MM). The sequence of merlin is similar to that of ezrin/radixin/moesin (ERM) proteins which crosslink actin with the plasma membrane, suggesting that merlin plays a role in transducing extracellular signals to the actin cytoskeleton. Merlin adopts a distinct closed conformation defined by specific intramolecular interactions and regulates diverse cellular events such as transcription, translation, ubiquitination, and miRNA biosynthesis, many of which are mediated through Hippo and mTOR signaling, which are known to be closely involved in cancer development. MM is a very aggressive tumor associated with asbestos exposure, and genetic alterations in NF2 that abrogate merlin's functional activity are found in about 40% of MMs, indicating the importance of NF2 inactivation in MM development and progression. In this review, we summarize the current knowledge of molecular events triggered by NF2/merlin inactivation, which lead to the development of mesothelioma and other cancers, and discuss potential therapeutic targets in merlin-deficient mesotheliomas.

In plain English

This article was a review, not a new study. The authors summarized published research on the NF2 gene, which makes a protein called merlin, and on how loss of merlin may contribute to malignant mesothelioma, a cancer they described as associated with asbestos exposure. They reported that genetic changes in NF2 are found in about 40% of mesotheliomas. From earlier studies, they described several findings. Mice with one faulty NF2 copy were more sensitive to asbestos. In an analysis of 211 malignant pleural mesothelioma samples, sarcomatoid tumors had the highest NF2 mutation rate and epithelioid tumors the lowest. In a cohort of 86 peritoneal mesothelioma patients, loss of one NF2 copy was reported to decrease overall and progression-free survival. The review described cell signaling pathways, including Hippo and mTOR, and possible drug targets. It noted that a phase II trial of the FAK inhibitor defactinib was stopped early for futility, and a phase II trial of everolimus showed insufficient activity. The authors concluded that targeting merlin-dependent pathways is a promising strategy, while noting that recent progress in NF2-targeted therapies had been limited.

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 clinical research
• Who was studied: No study population of its own. The review covered earlier studies of mesothelioma cells, tumors, mouse models and patients.
• Exposure: The review focused on inactivation of the NF2 gene (merlin loss), not on asbestos exposure. Asbestos was mentioned as associated with malignant mesothelioma, and no fiber types were named.
• Main results:
  • Genetic alterations in NF2 that abolish merlin's function were reported in about 40% of malignant mesotheliomas.
  • Citing earlier mouse studies: mice with one faulty NF2 copy (NF2+/-) had higher sensitivity to asbestos and an increased risk of malignant mesothelioma compared with normal mice.
  • Citing Bueno et al.: in 211 malignant pleural mesothelioma samples, sarcomatoid tumors had the highest NF2 mutation rate and epithelioid tumors the lowest.
  • Citing an earlier study: in a cohort of 86 peritoneal mesothelioma patients, hemizygous NF2 loss was shown to decrease both overall and progression-free survival.
  • A phase II trial of the FAK inhibitor defactinib in merlin-deficient mesotheliomas was terminated early due to futility.
  • A phase II trial of the mTOR inhibitor everolimus showed insufficient activity in patients with advanced mesothelioma.
• The authors' conclusion: The authors concluded that targeting merlin-dependent molecular pathways is a promising strategy for treating NF2-deficient cancers. They noted that recent progress in NF2-targeted therapies has been limited.
• Limitations the authors state:
  • The authors stated that progress in NF2-targeted therapies has been limited.
  • The authors stated that the clinical performance of the prospective drugs for restoring Hippo signaling or inhibiting the PI3K/AKT/mTOR pathway has not yet been evaluated.
  • The authors stated that the antitumor activity of newer mTOR inhibitors against mesothelioma has yet to be shown.

Topics

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

Medical terms in this study, explained in our Lexicon: Merlin, Mesothelioma, Malignant Mesothelioma, Asbestos Exposure.

Related studies

• Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation — Y. Sekido (2011)
• Functional inactivation of NF2/merlin in human mesothelioma — C. Thurneysen, I. Opitz, et al. (2009)
• E-cadherin expression is correlated with focal adhesion kinase inhibitor resistance in Merlin-negative malignant mesothelioma cells — T. Kato, T. Sato, et al. (2017)
• Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship — I.M. Shapiro, V.N. Kolev, et al. (2014)
• SORORIN and PLK1 as potential therapeutic targets in malignant pleural mesothelioma — T. Kato, D. Lee, et al. (2016)
• Merlin, a "magic" linker between extracellular cues and intracellular signaling pathways that regulate cell motility, proliferation, and survival — I. Stamenkovic, Q. Yu (2010)

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