Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib
Isocitrate dehydrogenase (IDH)-mutant gliomas have distinctive metabolic and biological traits that potentially render them susceptible to targeted treatments. Here, by conducting a high-throughput drug screen, we pinpointed a specific vulnerability of IDH-mutant gliomas to zotiraciclib (ZTR). ZTR exhibited selective growth inhibition across multiple IDH-mutant glioma <i>in vitro</i> and <i>in vivo</i> models. Mechanistically, ZTR at low doses suppressed CDK9 and RNA Pol II phosphorylation in IDH-mutant cells, disrupting mitochondrial function and NAD+ production, resulting in oxidative stress. Integrated biochemical profiling of ZTR kinase targets and transcriptomics unveiled that ZTR-induced bioenergetic failure was linked to the suppression of PIM kinase activity. We posit that the combination of mitochondrial dysfunction and an inability to adapt to oxidative stress resulted in significant cell death upon ZTR treatment, ultimately increasing the therapeutic vulnerability of IDH-mutant gliomas. These findings prompted a clinical trial evaluating ZTR in IDH-mutant gliomas (NCT05588141).
Authors
- Bao Tran (ORCID: https://orcid.org/0000-0002-0261-4458)
- Craig J. Thomas (ORCID: https://orcid.org/0000-0001-9386-9001)
- Felipe J. Núñez (ORCID: https://orcid.org/0000-0002-4962-3642)
- Taranjit S. Gujral (ORCID: https://orcid.org/0000-0002-4453-3031)
- Zach Sergi
- Ferri Soheilian
- Hua Song (ORCID: https://orcid.org/0000-0002-2791-1723)
- Michael M. Gottesman (ORCID: https://orcid.org/0000-0001-8908-2097)
- Herui Wang
- Li Qi (ORCID: https://orcid.org/0000-0001-6473-8117)
- Robert W. Robey (ORCID: https://orcid.org/0000-0002-0857-3650)
- Mark R. Gilbert (ORCID: https://orcid.org/0000-0003-2556-9722)
- Zheng-gang Liu (ORCID: https://orcid.org/0009-0009-3614-8836)
- Ying Pang (ORCID: https://orcid.org/0000-0001-6195-2150)
- Olga Kim (ORCID: https://orcid.org/0000-0002-4437-5870)
- Alice Ranjan (ORCID: https://orcid.org/0000-0003-4746-0170)
- Xueyu Sang
- María G. Castro (ORCID: https://orcid.org/0000-0003-2237-2756)
- Dionne L. Davis (ORCID: https://orcid.org/0000-0003-2880-8952)
- Wei Zhang (ORCID: https://orcid.org/0000-0001-5857-7230)
- Jing Wu (ORCID: https://orcid.org/0000-0002-4460-5322)
- Meili Zhang (ORCID: https://orcid.org/0000-0002-6970-6154)
- Peng Lu (ORCID: https://orcid.org/0009-0002-7120-5495)
- Marina Chan
- Guangyang Yu
Institutions
- National Institutes of Health (US)
- University of Michigan (US)
- Fred Hutch Cancer Center (US)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- National Center for Advancing Translational Sciences (US)
- Center for Cancer Research (US)
Publication Details
- Journal
- iScience
- Published
- 2025-03-25
- DOI
- https://doi.org/10.1016/j.isci.2025.112283
- Citations
- 2
- Primary Topic
- Neuroblastoma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.78
Funders
- Washington Research Foundation
- Ben and Catherine Ivy Foundation
- National Institutes of Health