Poster Session II. - E: Pathological and Oncological Sciences
Szőke Péter
Department of Pathology and Experimental Cancer Research, Semmelweis University
Péter Szőke1, Dániel Sztankovics1, Gergő Papp1, Ágnes Márk1, Anna Sebestyén1, Katalin Dezső1, Bálint Scheich1
1: Department of Pathology and Experimental Cancer Research, Semmelweis University
Introduction: Anaplastic meningiomas (CNS WHO grade 3) are aggressive tumors of the
meninges for wich effective therapies are currently unavailable. Recent studies highlight the
importance of epigenetic changes in their pathogenesis, notably the activation of Polycomb
Repressive Complex 2 (PRC2). However, the role of its catalytic subunit, the Enhancer of Zeste
Homolog 2 (EZH2), remains a question.
Aims: We aimed to analyze the characteristics of EZH2 expression in a cohort of grade 3
meningiomas and to investigate the effects of two EZH2 inhibitors, EPZ-6438 and MS-1943,
in the human meningioma cell lines IOMM-Lee and BEN-MEN-1 in vitro. EPZ-6438 is a
cofactor-competitive inhibitor of the methyltransferase activity of EZH2, while MS-1943 is an
EZH2 selective degrader.
Methods: EZH2 immunopositivity (H-score) was correlated with the clinical features, the
deletion of the chromosomal segment 9p21.3 and the loss of H3 K27me3 in our grade 3
meningioma samples (n=49). Effects of EPZ-6438 and MS-1943 on IOMM-Lee and BEN-
MEN-1 cell growth was assessed using the Alamar blue and sulforhodamine-B tests. Changes
in the cell cycle and cell death were analyzed using propidium iodide staining and flow
cytometry, while protein expression changes with WES Simple capillary immunoassay.
Results: In our cohort, elevated EZH2 expression correlated with poorer overall and local
progression-free survival, higher mitotic activity, and was higher in tumors with 9p21.3 deletion
and H3 K27me3 loss. EPZ-6438 reduced IOMM-Lee and BEN-MEN-1 cell growth dose-
dependently (10-40 µM), while MS-1943 was more potent at lower concentrations (1.25-5 µM).
The effects of both inhibitors were stronger in IOMM-Lee cells, where EPZ-6438 caused a
modest G0/G1 arrest, while MS-1943 also induced cell death. Both EPZ-6438 and MS-1943
increased p21 and decreased FOXM1 expression, while MS-1943 also induced p53
upregulation.
Conclusion: EZH2 overexpression plays a significant role in the aggressiveness of grade 3
meningiomas. MS-1943 demonstrates stronger inhibitory effects in cell growth in two distinct
meningioma cell lines in vitro than EPZ-6438. These results indicate that the non-conventional,
histone-methylation independent roles of EZH2 are essential and may represent more promising
targets for future therapeutic strategies in these tumors.
Funding: NKFIH-PD-146549.