Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib.

Background:Isocitrate dehydrogenase (IDH)-mutant gliomas exhibit unique metabolic and biological features that may make them vulnerable to specific treatment. In this study, we investigated the selective vulnerability of IDH-mutant gliomas to zotiraciclib (ZTR). Methods:We examined ZTR-induced cell death, mitochondrial dysfunction, and biogenesis defect at RNA, protein, and cellular levels. The survival benefit and pharmacodynamics of ZTR were evaluated using mouse models bearing mutant or wildtype IDH. Results:The IC 50 of ZTR in IDH-mutant patient-derived glioma cells was more than 50% lower than in IDH-wildtype cells. A high-throughput drug screen, utilizing a library of 2,481 approved and investigational drugs, provided independent evidence that ZTR was one of the most effective agents against IDH-mutant gliomas. ZTR-induced suppression of CDK9 and RNA Pol II phosphorylation was more pronounced in IDH-mutant cells. Low-dose ZTR (15 nM) suppressed mitochondrial respiration complexes and NAD+ production, leading to oxidative stress in IDH-mutant but not in IDH-wildtype cells. Furthermore, ZTR exposure resulted in a decrease in glycolysis, exacerbating bioenergetic failure. Finally, ZTR significantly prolonged the survival of mice bearing intracranial IDH-mutant gliomas but not in the IDH-wildtype counterpart. The combination of mitochondrial dysfunction and the inability to adapt to oxidative stress leads to potent ZTR-induced cell death and thereby an increased therapeutic vulnerability in IDH-mutant gliomas. Conclusions:The findings led to the launch of a clinical trial of ZTR in IDH-mutant gliomas towards precision medicine ( NCT 05588141 ).