CUDC907, a dual phosphoinositide-3 kinase/histone deacetylase inhibitor, promotes apoptosis of NF2 Schwannoma cells

Abstract

// Julianne Huegel 1 , Christine T. Dinh 2 , Maria Martinelli 1 , Olena Bracho 2 , Rosa Rosario 1 , Haley Hardin 1 , Michael Estivill 2 , Anthony Griswold 3 , Sakir Gultekin 4 , Xue-Zhong Liu 2 , 5 and Cristina Fernandez-Valle 1 1 Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA 2 Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, FL 33136, USA 3 John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA 4 Department of Pathology, University of Miami Miller School of Medicine, Miami, FL 33136, USA 5 Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA Correspondence to: Cristina Fernandez-Valle, email: [email protected] Keywords: fimepinostat; Schwann cell; vestibular schwanomma; merlin; nerve allograft Received: May 24, 2022     Accepted: June 28, 2022     Published: July 19, 2022 Copyright: © 2022 Huegel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Neurofibromatosis Type 2 (NF2) is a rare tumor disorder caused by pathogenic variants of the merlin tumor suppressor encoded by NF2 . Patients develop vestibular schwannomas (VS), peripheral schwannomas, meningiomas, and ependymomas. There are no approved drug therapies for NF2. Previous work identified phosphoinositide-3 kinase (PI3K) as a druggable target. Here we screened PI3K pathway inhibitors for efficacy in reducing viability of human schwannoma cells. The lead compound, CUDC907, a dual histone deacetylase (HDAC)/PI3K inhibitor, was further evaluated for its effects on isolated and nerve-grafted schwannoma model cells, and primary VS cells. CUDC907 (3 nM IG 50 ) reduced human merlin deficient Schwann cell (MD-SC) viability and was 5–100 fold selective for MD over WT-SCs. CUDC907 (10 nM) promoted cell cycle arrest and caspase-3/7 activation within 24 h in human MD-SCs. Western blots confirmed a dose-dependent increase in acetylated lysine and decreases in pAKT and YAP. CUDC907 decreased tumor growth rate by 44% in a 14-day treatment regimen, modulated phospho-target levels, and decreased YAP levels. In five primary VS, CUDC907 decreased viability, induced caspase-3/7 cleavage, and reduced YAP levels. Its efficacy correlated with basal phospho-HDAC2 levels. CUDC907 has cytotoxic activity in NF2 schwannoma models and primary VS cells and is a candidate for clinical trials.

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