R132H IDH1 sensitizes glioma to the antiproliferative and cytotoxic effects of BET inhibition

INTRODUCTION: Mutations in isocitrate dehydrogenase 1/2 (IDH(mut)) identify a subset of gliomas that exhibit epigenetic dysregulation via aberrant DNA methylation. These tumors are ultimately fatal and lack effective therapeutic strategies. Considering the epigenetic dysregulation of IDH(mut) gliomas, we hypothesized that epigenetic-targeting drugs may yield therapeutic benefits in gliomas bearing IDH(mut). One set of targets includes the bromodomain and extraterminal (BET) family of transcriptional coactivators. METHODS: We used TCGA data from glioma patients to determine whether BET proteins affect patient survival differently based on IDH status. Follow-up experiments using a set of IDH wildtype/mutant glioma cultures, as well as an IDH wildtype glioblastoma cell line expressing exogenous R132H IDH1, focused on cell health assays to investigate whether IDH(mut) was associated with increased sensitivity to the BET inhibitor JQ1. Immunoblots were used to evaluate the molecular response to JQ1 in these cultures. RESULTS: We identified that high BRD4 expression associated with decreased survival only in IDH(mut) glioma patients. Cell viability analysis showed that IDH(mut) sensitized glioma cells to delayed cytotoxicity (10 days) in response to JQ1. Early effects of JQ1 (3 days) were primarily antiproliferative, with IDH(mut) glioma exhibiting a modest increase in sensitivity. Finally, exogenous R132H IDH1 expression in a resistant IDH wildtype cell line recapitulated the JQ1-mediated delayed cytotoxicity seen in our endogenous IDH(mut) glioma cells. CONCLUSION: Overall, these data suggest that BRD4 enhances malignancy primarily in gliomas bearing IDH(mut) and is associated with greater sensitivity to BET inhibition. The finding that BET inhibition primarily exhibits delayed cytotoxicity may be overlooked in conventional short endpoint dose–response assays. Follow-up mechanistic and animal studies will help address the translational potential of these findings. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00432-022-04018-w.