EZH2 inhibition sensitizes IDH1R132H mutant gliomas to Panobinostat

Isocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and prognosis, however its role in glioma development, and its impact on response to therapy, is not fully understood. We developed a murine model of proneural IDH1R132H mutated glioma that shows elevated production of 2-Hydroxyglutarate (2-HG) and increased tri-methylation of lysine residue K27 on histone H3 (H3K27me3) compared to IDH1 wild-type tumors. We found that using Tazemetostat to inhibit the methyltransferase for H3K27, Enhancer of Zeste 2 (EZH2), reduced H3K27me3 levels and increased acetylation on H3K27. We also found that, although the histone deacetylase inhibitor (HDACi) Panobinostat was less cytotoxic in IDH1R132H mutated cells (either isolated from murine glioma or oligodendrocyte progenitor cells infected in vitro with a retrovirus expressing IDH1R132H) compared to IDH1-wildtype cells, co-treatment with Tazemetostat is synergistic in both mutant and wildtype models. These findings indicate a novel therapeutic strategy for IDH1-mutated gliomas that targets the specific epigenetic alteration in these tumors. Overall design: To determine the effect of IDH1 R132H mutation on gliomagenesis, we established an in vivo and in vitro model for both mutant and wildtype IDH1 murine gliomas initated by targeting glial progenitors of the subcortical white matter. We performed transcriptional profiling by RNA-seq on the IDH1R132H mutant and wildtype tumors to determine if these tumors would recapitulate the molecular profile of human proneural gliomas from the Verhaak et al. subtype classifers gene signatures. We compared the expression profile of the wildtype (N=5) and IDH1R132H (n=6) endstage murine tumors to the TCGA database using Gene Set Enrichment Analysis (GSEA),