Validation of Bromodomain and Extraterminal proteins as therapeutic targets in neurofibromatosis type 2

• Published in: Neuro-oncology advances 2022-01, Vol.4 (1), p.vdac072-vdac072
• Main Authors: Doherty, Joanne, Mandati, Vinay, González Rodriguez, Maria A, Troutman, Scott, Shepard, Alyssa, Harbaugh, David, Brody, Rachel, Miller, Douglas C, Kareta, Michael S, Kissil, Joseph L
• Format: Article
• Language: English
• Subjects: Basic and Translational Investigations
• ISSN: 2632-2498; 2632-2498
• DOI: 10.1093/noajnl/vdac072

Abstract Background Neurofibromatosis type 2 (NF2) is an autosomal dominant genetic disease characterized by development of schwannomas on the VIIIth (vestibular) cranial nerves. Bromodomain and extra-terminal domain (BET) proteins regulate gene transcription and their activity is required in a variety of cancers including malignant peripheral nerve sheath tumors. The use of BET inhibitors as a therapeutic option to treat NF2 schwannomas has not been explored and is the focus of this study. Methods A panel of normal and NF2-null Schwann and schwannoma cell lines were used to characterize the impact of the BET inhibitor JQ1 in vitro and in vivo. The mechanism of action was explored by chromatin immunoprecipitation of the BET BRD4, phospho-kinase arrays and immunohistochemistry (IHC) of BRD4 in vestibular schwannomas. Results JQ1 inhibited proliferation of NF2-null schwannoma and Schwann cell lines in vitro and in vivo. Further, loss of NF2 by CRISPR deletion or siRNA knockdown increased sensitivity of cells to JQ1. Loss of function experiments identified BRD4, and to a lesser extent BRD2, as BET family members mediating the majority of JQ1 effects. IHC demonstrated elevated levels of BRD4 protein in human vestibular schwannomas. Analysis of signaling pathways effected by JQ1 treatment suggests that the effects of JQ1 treatment are mediated, at least in part, via inhibition of PI3K/Akt signaling. Conclusions NF2-deficient Schwann and schwannoma cells are sensitive to BET inhibition, primarily mediated by BRD4, which is overexpressed in human vestibular schwannomas. Our results suggest BRD4 regulates PI3K signaling and likely impedes NF2 schwannoma growth via this inhibition. These findings implicate BET inhibition as a therapeutic option for NF2-deficient schwannomas.