The Role of EZH2 ın Malıgnant Pleural Mesothelıoma and Beyond: Current Practıce and Future Perspectıves

Our plain-English summary of The Role of EZH2 ın Malıgnant Pleural Mesothelıoma and Beyond: Current Practıce and Future Perspectıves, by M. Kucukoner, T. Demir, A.M. Alsubaie, et al (Current Oncology Reports, 2026).

The study

• Authors: M. Kucukoner, T. Demir, A.M. Alsubaie, U. Alabalik, A.K. Ibrahim, M. Pierobon, L. Liotta
• Journal: Current Oncology Reports
• Published: 2026;28(1)
• Type of article: Review
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose Of Review: Malignant pleural mesothelioma (MPM) remains a rare but highly aggressive malignancy with limited treatment options and poor prognosis. For nearly twenty years, platinum-pemetrexed chemotherapy has persisted as the unchanged standard treatment; although recent progress in immunotherapy has modestly disrupted this therapeutic plateau, survival outcomes remain disappointingly limited. This review aims to provide a comprehensive overview of the epigenetic landscape of MPM, focusing particularly on the oncogenic and therapeutic implications of enhancer of zeste homolog 2 (EZH2), and to discuss its potential as a target for novel therapeutic strategies and combination regimens.

Recent Findings: Epigenetic dysregulation has emerged as a central driver of mesothelioma pathogenesis. EZH2, the catalytic component of the polycomb repressive complex 2 (PRC2), mediates histone H3K27 trimethylation, silencing tumor suppressor genes and promoting malignant transformation. In addition to its canonical role, EZH2 has non-canonical oncogenic effects that modulate transcription, apoptosis, DNA repair, and immune evasion. High EZH2 expression correlates with BAP1 loss, which enhances chromatin remodeling defects and disease aggressiveness. Preclinical and early clinical data demonstrate that EZH2 inhibitors-including tazemetostat, valemetostat, GSK126, EPZ011989, tulmimetostat, and novel PROTAC-based degraders such as MS1943-can suppress tumor progression, modulate the tumor immune microenvironment, and restore therapeutic sensitivity. Furthermore, combination approaches integrating EZH2 inhibition with chemotherapy or immune checkpoint blockade show synergistic potential in overcoming resistance. EZH2 represents a pivotal epigenetic regulator and a promising therapeutic target in MPM. Further understanding the dual canonical and non-canonical roles of EZH2 in tumor biology will be key to optimizing targeted and combinatorial treatment strategies. Future research should focus on translating EZH2 inhibition into clinical benefit, identifying predictive biomarkers of response, and exploring rational combinations with chemotherapy, targeted drugs, or immunotherapy to improve survival outcomes in mesothelioma patients.

© 2026. The Author(s).

In plain English

This article was a narrative review, not a new study. The authors stated that no datasets were generated or analysed. It reviewed laboratory and clinical research on EZH2 in malignant pleural mesothelioma (MPM); EZH2 is a protein that switches genes off and, the authors noted, may also switch some genes on. The authors described MPM as associated with asbestos exposure, but asbestos was not studied. One summarized study was a phase II trial of tazemetostat in 74 patients with relapsed or refractory MPM. It reported a disease control rate of 54% in the BAP1-inactivated tumor cohort and 51% in the other cohort. A preliminary report on tulmimetostat described 21 patients with BAP1-loss pleural mesothelioma: 14% had a partial response and 48% had stable disease. Cited animal and cell studies reported tumor shrinkage in BAP1-mutant mesothelioma models with EZH2 inhibitors, alone or combined with other drugs. The authors concluded that clinical studies in mesothelioma are limited but preclinical results are promising. They noted there are no phase III tazemetostat trials in mesothelioma, and that drug resistance may limit EZH2 inhibitors used alone.

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 preclinical and clinical studies; no new data were collected
• Who was studied: Published laboratory (cell line and animal) studies and clinical trials of EZH2 inhibitors, mainly in malignant pleural mesothelioma, plus trials in other solid tumors listed in tables of completed and ongoing trials
• Exposure: Not an exposure study. The exposures reviewed were EZH2-targeting drugs (tazemetostat, valemetostat, GSK126, EPZ011989, tulmimetostat, MS1943, EED226). Asbestos was mentioned only as background to the cause of mesothelioma.
• Main results:
  • The review described EZH2 as having both a gene-silencing role and a gene-activating role
  • In a cited phase II trial of tazemetostat that included 74 patients with MPM, the disease control rate was 54% in the BAP1-inactivated tumor cohort and 51% in the other cohort
  • In that tazemetostat trial, the most common adverse events were fatigue, decreased appetite and nausea
  • In a cited phase 1/2 study of tulmimetostat, the cohort with BAP1-loss pleural mesothelioma had 21 patients evaluated: 14% had a partial response and 48% had stable disease, a disease control rate of 62%
  • A cited study reported EZH2 expression in MPM at rates as high as 85% compared with normal mesothelial cells
  • In cited preclinical studies, EPZ011989 reduced tumour size by 60–70% in BAP1-mutant tumors
  • In a cited preclinical study, GSK126 combined with the ATM inhibitor AZD1390 reduced tumor volume by approximately 60% in BAP1-mutant mesothelioma tumors
  • A cited study found that GSK126 treatment increased myeloid-derived suppressor cells, which suppress immune responses against the tumor
• The authors' conclusion: The authors concluded that EZH2-specific clinical studies in mesothelioma are limited but preclinical results are promising. They suggested that next-generation EZH2 inhibitors, combined with immunotherapy, targeted therapy or chemotherapy, may have the potential to improve survival.
• Limitations the authors state:
  • No phase III trials have specifically evaluated tazemetostat in mesothelioma
  • No clinical trials have evaluated EPZ011989 in mesothelioma patients
  • Resistance mechanisms may limit the use of EZH2 inhibitors alone

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, Prognosis, Platinum-Pemetrexed, Chemotherapy, Immunotherapy, Mesothelioma, Tumor Suppressor Gene, Malignant Transformation.

Related studies

• Highly expressed EZH2 in combination with BAP1 and MTAP loss, as detected by immunohistochemistry, is useful for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia — M. Yoshimura, Y. Kinoshita, et al. (2019)
• Tazemetostat: First Approval — S.M. Hoy (2020)
• Diagnostic utility of BAP1 and EZH2 expression in malignant mesothelioma — A. Shinozaki-Ushiku, T. Ushiku, et al. (2017)
• Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids — S. Mola, G. Pinton, et al. (2021)
• Complex Immune Contextures Characterise Malignant Peritoneal Mesothelioma: Loss of Adaptive Immunological Signature in the More Aggressive Histological Types — M. Tazzari, S. Brich, et al. (2018)
• Combination of EZH2 and ATM inhibition in BAP1-deficient mesothelioma — N. Landman, D. Hulsman, et al. (2024)

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