877 EZH2 Inhibition Decreases SMARCB1 and NF2 Mutant Meningioma Cell Viability. (April 2023)

• Record Type: Journal Article
• Authors: Clark, Victoria Elizabeth; Young, Richard
• Is Part Of: Neurosurgery. Volume 69(2023)Supplement 1
• Page Start: 49
• Page End: 49
• Publication Date: 2023-04
• Subjects: Nervous system -- Surgery -- Periodicals; 617.48005
• DOI: 10.1227/neu.0000000000002375_877
• Languages: English
• ISSNs: 0148-396X

Abstract

Abstract : INTRODUCTION: The majority of sporadic and familial forms of meningiomas bear mutations in NF2. A subset of NF2 mutant meningiomas are co-mutant for SMARCB1, which encodes the SWI/SNF complex core subunit BAF47, grow in the midline/parafalcine region, and confer risk for atypia. SMARCB1/NF2 meningiomas and WHO Grade II NF2 meningiomas have demonstrated PRC2/EZH2 hyperactivity by ChIPseq analysis, providing a rationale for EZH2 inhibition for these aggressive tumors. METHODS: Pharmacologic growth inhibition experiments were conducted in a SMARCB1/NF2 co-mutant meningioma cell line (BEN-MEN-1), an NF2 mutant/SMARCB1 wildtype meningioma cell line (MN1-LF), and a control wildtype arachnoid cell line (A2). Tazemetostat was administered in triplicate at 9 dosages (ranging from 1.5 uM to 10 mM) over 14 days. Cell viability was calculated via luminescent-based assay and normalized to DMSO-treated cells. RESULTS: After 14 days of tazemetostat treatment, SMARCB1/NF2 mutant cells showed a significantly decreased viability compared to control arachnoid cells (26.87% viability for SMARCB1 mutant vs 87.80% viability for arachnoid cells; p = 0.0047). NF2 mutant meningioma cells also had significantly decreased viability (48.84% vs 87.80%, p = 0.0102). The calculated IC50 for tazemetostat is 3.098 mM for SMARCB1/NF2 mutant cells, 6.263 mM for NF2 mutant cells, and was estimated to be 43.98 mM in control arachnoid cells using nonlinear regression. CONCLUSIONS: Tazemetostat decreases viability for both SMARCB1/NF2 and NF2 mutant meningioma cells. This represents a novel pharmacologic target for the majority of meningiomas, and may obviate the need for repeat surgery for recurrent tumors or serve as a suppressant agent for patients with neurofibromatosis type II.