Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib

Author:

Pang, Ying

Li, Qi

Sergi, Zach

Yu, Guangyang

Kim, Olga

Lu, Peng

Chan, Marina

Sang, Xueyu

Wang, Herui

Ranjan, Alice

Robey, Robert W

Soheilian, Ferri

Tran,Bao

Núñez, Felipe J

Zhang, Meili

Song, Hua

Zhang, Wei

Davis, Dionne

Gilbert, Mark R

Gottesman, Michael M

Liu, Zhenggang

Thomas, Craig J

Castro, Maria G

Gujral, Taranjit S

Wu, Jing
Author Address

Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA., Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Electron Microscopy Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21701, USA., Cancer Research Technology Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 20701, USA., Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Rockville, MD 20850, USA.,

Abstract:

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 in 160;vitro and in 160;vivo 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).

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Author Address