GSE134120
Combination of epigenetic enzyme inhibitors, GSKJ4 and Belinostat, reveals efficacy in IDH1 mutant gliomas
Mutations in IDH1 and IDH2 genes are very common in low grade gliomas and secondary GBM. They induce hypermethylation of DNA and histones in tumor cells, and generate a specific epigenetic phenotype. Therefore, we decided to perform a chemical screen consisting of inhibitors of epigenetic regulators on patient-derived IDH mutant cell lines. Dual combinations of hit inhibitors in low doses were also analyzed to increase treatment efficiency. Individual and combinatorial effects of these inhibitors were also analyzed in wild type and IDH mutant pair of A172 GBM cell line that was derived by ectopic overexpression of mutant IDH1. GSK-J4 and Belinostat combination was highly effective on both patient-derived and engineered IDH mutant cells compared to wild type cells. Interestingly, sensitized IDH mutant cells were recovered via mutant IDH inhibitor, GSK864, which is thought as a candidate drug for IDH mutant glioma. On the other hand, viability of non-malignant fibroblasts were not affected from these drugs in these doses. GSK-J4 and Belinostat combination induce apoptosis which was shown by increased Caspase 3/7 activity, PARP cleavage and recovery with general caspase inhibitor (Z-VAD-FMK). Change in histone modifications such as H3K4me3, H3K9me3, H3K27me3 and H3K27ac were observed after mutant IDH overexpression and also drug treatments. RNA-seq and GSEA analysis revealed activation of unfolded protein and viral response pathways in IDH mutant cells which indicate increased cell stress. GSKJ4 and Belinostat induces cell cycle arrest and apoptosis by further increasing cell stress probably because of dramatic changes in chromatin structure. Overall design: mRNA profile of A172 WT and IDH mutant cells either with GSK864 (mutant IDH inhibitor) treatment or not. Another mRNA profiling from MGG152 patient derived IDH mutant cells either without treatment, or treated with GSK-J4 alone, Belinostat alone or both in combination