Molecular Alterations in Malignant Pleural Mesothelioma: A Hope for Effective Treatment by Targeting YAP

Our plain-English summary of Molecular Alterations in Malignant Pleural Mesothelioma: A Hope for Effective Treatment by Targeting YAP, by F. Dubois, C. Bazille, J. Levallet, et al (Targeted Oncology, 2022).

The study

• Authors: F. Dubois, C. Bazille, J. Levallet, E. Maille, S. Brosseau, J. Madelaine, E. Bergot, G. Zalcman, G. Levallet
• Journal: Targeted Oncology
• Published: 2022;17(4):407-431
• Type of article: Review
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma is a rare and aggressive neoplasm, which has primarily been attributed to the exposure to asbestos fibers (83% of cases); yet, despite a ban of using asbestos in many countries, the incidence of malignant pleural mesothelioma failed to decline worldwide. While little progress has been made in malignant pleural mesothelioma diagnosis, bevacizumab at first, then followed by double immunotherapy (nivolumab plus ipilumumab), were all shown to improve survival in large phase III randomized trials. The morphological analysis of the histological subtyping remains the primary indicator for therapeutic decision making at an advanced disease stage, while a platinum-based chemotherapy regimen combined with pemetrexed, either with or without bevacizumab, is still the main treatment option. Consequently, malignant pleural mesothelioma still represents a significant health concern owing to poor median survival (12-18 months). Given this context, both diagnosis and therapy improvements require better knowledge of the molecular mechanisms underlying malignant pleural mesothelioma's carcinogenesis and progression. Hence, the Hippo pathway in malignant pleural mesothelioma initiation and progression has recently received increasing attention, as the aberrant expression of its core components may be closely related to patient prognosis. The purpose of this review was to provide a critical analysis of our current knowledge on these topics, the main focus being on the available evidence concerning the role of each Hippo pathway's member as a promising biomarker, enabling detection of the disease at earlier stages and thus improving prognosis.

© 2022. The Author(s).

In plain English

This article was a literature review, not a new study of patients. The authors described malignant pleural mesothelioma as largely attributed to environmental or occupational asbestos exposure (83% of cases). It focused on the Hippo cell-signaling pathway and its end protein, YAP. Citing other studies, the authors reported loss-of-function NF2 gene mutations in 20–50% of cases and RASSF1 promoter hypermethylation in 10–32%, which was associated with shorter survival. They reported LATS2 deletion or mutation in 12% of tumor samples and constitutive YAP activation in 59% of patients tested. In the authors' earlier study of 223 trial tumor samples, the MST1 promoter was methylated in 19 (8.5%). Those patients' median overall survival was 1.4-fold lower than that of patients with an unmethylated MST1 promoter. The authors concluded that Hippo pathway alterations are common in this cancer but that the pathway's role is still unclear. They suggested that two kinds of screening could be a foundation for possible early detection in follow-up of previously asbestos-exposed workers: screening tissue for abnormal promoter methylation of Hippo pathway components, or screening circulating microRNAs that regulate the pathway.

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 literature review (no new data generated)
• Who was studied: Published research on malignant pleural mesothelioma, with a focus on the Hippo signaling pathway; no patients were studied directly for this article
• Exposure: Asbestos fibers in general (no specific fiber types named), described as the cause attributed in 83% of malignant pleural mesothelioma cases; the review's focus was molecular alterations rather than exposure
• Main results:
  • From cited studies: loss-of-function NF2 mutations in 20–50% of malignant pleural mesothelioma cases, depending on the molecular technique used
  • From cited studies: RASSF1 gene promoter hypermethylation in 10–32% of malignant pleural mesotheliomas, associated with shorter overall survival
  • From the authors' group's earlier study of 223 samples from patients in the MAPS (IFCT-GFPC-0701) phase III trial: MST1 promoter methylated in 19/223 samples (8.5%), with median overall survival 1.4-fold lower than in patients with an unmethylated MST1 promoter
  • In the same earlier study, methylation of RASSF1A, RASSF2A, RASSF6 and RASSF10 (11.1%, 14.5%, 21.5% and 4.4% of samples) did not influence patient survival in univariate analysis
  • From a cited study: inactivating homozygous deletion or point mutation of LATS2 in 12% of malignant pleural mesothelioma tumor samples (35% of cell lines)
  • From a cited study: YAP constitutively activated in 59% of malignant pleural mesothelioma patients tested
  • In the authors' own cell-line work, inactivating both YAP and RASSF1A in mesothelial (H28, H2052) or bronchial (HBEC-3) cell lines did not prevent all the cell disorders caused by disrupting the pathway
• The authors' conclusion: The authors concluded that Hippo pathway alterations are common and multiple in malignant pleural mesothelioma, but that the pathway's essential role in the natural history of the disease is still unclear. They described the pathway as a promising biomarker for earlier detection. They suggested that systematic screening of abnormal promoter methylation of Hippo pathway components in tissue samples, or of circulating microRNAs that regulate the pathway, is likely to be a relevant foundation for possible monitoring and early detection in the follow-up of workers previously exposed to asbestos.
• Limitations the authors state:
  • The authors stated that the necessary tools are still lacking
  • The authors noted that the siRNAs used in their own experiments did not inactivate all YAP variants (isoforms)

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: Pleural Mesothelioma, Neoplasm, Bevacizumab, Immunotherapy, Nivolumab (Opdivo), Chemotherapy, Pemetrexed (Alimta), Median Survival.

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