EXTH-28 - Isocitrate dehydrogenase mutations predict sensitivity to histone deacetylase inhibition and enhanced histone acetylation dynamics only in the context of glioma

Isocitrate dehydrogenase 1/2 mutations (IDH^mut) define a subtype of glioma with profound epigenetic dysregulation through genomic hypermethylation. IDH^mut gliomas are incurable and fatal, demonstrating new treatments are needed. These mutations are common in other solid tumors, including chondrosarcoma (CS) and intrahepatic cholangiocarcinoma (ICC). Histone deacetylase (HDAC) enzymes compose a class of epigenetic drug targets utilized clinically to treat cancer, but their potential against IDH^mut gliomas has not been extensively studied. We previously showed that IDH^mut glioma cultures exhibit pronounced sensitivity to the effects mediated by the FDA-approved HDAC inhibitor (HDACi) panobinostat. Here, we integrate proliferation and cytoxicity data to show that this effect is unique to gliomas. In the context of histone H3 acetylation (H3KAc), panobinostat increased H3KAc, on average, by 7.6-fold and 30.5-fold in IDH^wt and IDH^mut glioma cultures, respectively (p < 0.001). This difference in HDACi-mediated H3KAc based on IDH status was not significant for CS and ICC. IDH^mut gliomas are more sensitive two other FDA-approved HDACis: belinostat and vorinostat. RNA-Seq analysis showed that panobinostat more greatly affected gene expression in IDH^mut glioma cells, particularly in the context of gene downregulation. Similarly, H3KAc ChIP-Seq showed a decrease in promoter histone acetylation moreso in IDH^mut glioma cultures treated with panobinostat: there is an average loss of 1,236 and 14,759 H3KAc peaks at gene promoters in IDH^wt and IDH^mut cultures, respectively. This suggests that IDH^mut gliomas exhibit enhanced histone acetylation dynamics in response to HDACi. Furthermore, using a PDX glioma model, we show that only mice engrafted with IDH^mut glioma exhibit a significant survival increase in response to the HDACi belinostat: median survival was extended by 14 days in IDH^mut glioma-bearing mice (p= 0.01), whereas belinostat extended median survival by 4 days in IDH^wt glioma-bearing mice (p= 0.11). These results suggest that HDACi may be an effective in treating IDH^mut gliomas.