Fimepinostat Promotes Apoptosis and Decreases Cytokine Secretion in NF2-Related Human Schwannoma Cells

TL;DR

Fimepinostat, a drug that inhibits HDAC and PI3K, shows promise in reducing tumor size and promoting cell death in schwannomas related to NF2-related schwannomatosis.

Contribution

The study demonstrates fimepinostat's efficacy in promoting apoptosis and reducing cytokine secretion in NF2-related schwannoma cells.

Findings

Fimepinostat induces p21-dependent cell cycle inhibition and upregulates TRAIL R2 in schwannoma cells.

The drug downregulates TNFR1, YAP, and apoptosis inhibitors, leading to caspase-3-dependent apoptosis.

Fimepinostat reduces cytokine and chemokine secretion caused by merlin loss in schwannoma cells.

Abstract

This study focuses on the action of fimepinostat, a dual histone deacetylase (HDAC)/phosphosphoinositide-3 kinase (PI3K) inhibitor in NF2-related schwannomatosis. Decreased tumor sized in a mouse sciatic nerve allograft model accompanied with mechanistic studies on human model cell lines suggests that HDAC inhibition might be a feasible antitumor therapy in NF2-related schwannomatosis.

There is no approved drug therapy for schwannomas associated with NF2-related schwannomatosis (NF2-SWN). Neither life-saving surgical resection or radiation are curative and can compound the debilitating neurological effects of the schwannomas. We previously identified fimepinostat, a dual histone deacetylase (HDAC)/phosphoinositide-3 kinase (PI3K) inhibitor, as a promising drug candidate with pro-apoptotic effects on NF2-related schwannomas. This preclinical study used the pharmaceutical formulation of fimepinostat to confirm its efficacy in schwannomas and identify pro-apoptotic signaling pathways. Fimepinostat was tested in human schwannoma model cells, patient-derived primary vestibular and non-vestibular schwannoma cells, and in a sciatic nerve allograft model. The signaling pathways leading to caspase-3-dependent apoptosis were elucidated using immune assays, flow cytometry, imaging, proteome, and acetylome analysis. Acute exposure to fimepinostat led to p21-dependent cell cycle inhibition, upregulation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL R2), and downregulation of tumor necrosis factor receptor 1 (TNFR1), Yes-associated protein (YAP), and inhibitors of apoptosis. Moreover, fimepinostat downregulated cytokine and chemokine secretion increased by merlin loss in schwannoma cells. Fimepinostat is a promising new drug intervention for NF2-SWN patients with the potential to promote tumor regression.

Figures