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 IG50) 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.