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

Abstract

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.

Keywords: Bromodomain and extraterminal (BET); Bromodomain inhibition; Glioma; JQ1; Mutant isocitrate dehydrogenase 1/2 (IDH1/2).