Combined inhibition of KDM6A/B and HDACs exacerbates integrated stress response and mediates therapeutic effects in IDH1-mutant glioma

IDH1/2 -mutant gliomas are primary brain tumors for which curative treatments are lacking. Using a chemical screen targeting chromatin modifiers, we identified the histone H3 K27me3 demethylase inhibitor GSK-J4 and class I histone deacetylase inhibitors such as Belinostat as potent, genotype-selective agents against IDH1 -mutant glioma. RNA-sequencing on paired wild-type and IDH1 R132H cells revealed induction of stress-related pathways in IDH1 R132H cells, which was dependent on the onco-metabolite 2-hydroxyglutarate (2-HG). GSK-J4 and Belinostat combination activated an ATF4-mediated integrated stress response, cell cycle arrest, and DDIT3 /CHOP-dependent apoptosis in IDH1 -mutant cells. We show that genetic ablation of GSK-J4 target histone demethylases, KDM6A and KDM6B phenocopied the pharmacological effects of the compound. Combination treatment of GSK-J4 and Belinostat extended animal survival in an IDH1 -mutant orthotopic model in vivo . These results provide a possible therapeutic approach that exploits epigenetic vulnerabilities of IDH -mutant gliomas. Statement of Significance IDH1/2 genes are frequently mutated in low grade glioma and secondary glioblastoma. These tumors exhibit a distinct epigenome with increased DNA and histone methylation; therefore, identifying and exploiting their epigenetic vulnerabilities may lead to effective therapies. We discover targeting of KDM6A/6B together with HDACs provides a promising genotype-specific therapeutic approach. ### Competing Interest Statement The authors have declared no competing interest.