Title: Vulnerability of IDH1-Mutant Cancers to Histone Deacetylase Inhibition via Orthogonal Suppression of DNA Repair.

Authors: Dow, Jonathan; Krysztofiak, Adam; Liu, Yanfeng; Colon-Rios, Daniel A; Rogers, Faye A; Glazer, Peter M

Published In Mol Cancer Res, (2021 12)

Abstract: Exploitation of DNA repair defects has enabled major advances in treating specific cancers. Recent work discovered that the oncometabolite 2-hydroxyglutarate (2-HG), produced by neomorphic isocitrate dehydrogenase 1/2 (IDH1/2) mutations, confers a homology-directed repair (HDR) defect through 2-HG-induced histone hypermethylation masking HDR signaling. Here, we report that IDH1-mutant cancer cells are profoundly sensitive to the histone deacetylase inhibitor (HDACi) vorinostat, by further suppressing the residual HDR in 2-HG-producing cells. Vorinostat downregulates repair factors BRCA1 and RAD51 via disrupted E2F-factor regulation, causing increased DNA double-strand breaks, reduced DNA repair factor foci, and functional HDR deficiency even beyond 2-HG's effects. This results in greater cell death of IDH1-mutant cells and confers synergy with radiation and PARPi, both against cells in culture and patient-derived tumor xenografts. Our work identifies HDACi's utility against IDH1-mutant cancers, and presents IDH1/2 mutations as potential biomarkers to guide trials testing HDACi in gliomas and other malignancies. IMPLICATIONS: IDH1-mutant cells show profound vulnerability to HDACi treatment, alone and with PARPi and radiation, via HDR suppression, presenting IDH1/2 mutations as biomarkers for HDACi use in gliomas and other malignancies.

PubMed ID: 34535560

MeSH Terms: Animals; Cell Line, Tumor; DNA Repair/genetics*; Glioma/drug therapy*; Histone Deacetylase Inhibitors/pharmacology; Histone Deacetylase Inhibitors/therapeutic use*; Humans; Isocitrate Dehydrogenase/metabolism*; Mice; Mice, Nude