Exploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile

Exploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile

Abstract Glioblastoma is one of the most treatment-resistant and lethal cancers, with a subset of self-renewing brain tumour stem cells (BTSCs), driving therapy resistance and relapse. Here, we report that mubritinib effectively impairs BTSC stemness and growth. Mechanistically, bioenergetic assays...

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Main Authors: Audrey Burban, Cloe Tessier, Mathieu Larroquette, Joris Guyon, Cloe Lubiato, Mathis Pinglaut, Maxime Toujas, Johanna Galvis, Benjamin Dartigues, Emmanuelle Georget, H Artee Luchman, Samuel Weiss, David Cappellen, Nathalie Nicot, Barbara Klink, Macha Nikolski, Lucie Brisson, Thomas Mathivet, Andreas Bikfalvi, Thomas Daubon, Ahmad Sharanek
Format: Article
Language:English
Published: Springer Nature 2025-02-01
Series:EMBO Molecular Medicine
Subjects:
Metabolic Reliance
Oxidative Phosphorylation
Radiotherapy
Hypoxia
Reactive Oxygen Species
Online Access:https://doi.org/10.1038/s44321-025-00195-6
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Summary:Abstract Glioblastoma is one of the most treatment-resistant and lethal cancers, with a subset of self-renewing brain tumour stem cells (BTSCs), driving therapy resistance and relapse. Here, we report that mubritinib effectively impairs BTSC stemness and growth. Mechanistically, bioenergetic assays and rescue experiments showed that mubritinib targets complex I of the electron transport chain, thereby impairing BTSC self-renewal and proliferation. Gene expression profiling and Western blot analysis revealed that mubritinib disrupts the AMPK/p27Kip1 pathway, leading to cell-cycle impairment. By employing in vivo pharmacokinetic assays, we established that mubritinib crosses the blood-brain barrier. Using preclinical patient-derived and syngeneic models, we demonstrated that mubritinib delays glioblastoma progression and extends animal survival. Moreover, combining mubritinib with radiotherapy or chemotherapy offers survival advantage to animals. Notably, we showed that mubritinib alleviates hypoxia, thereby enhancing ROS generation, DNA damage, and apoptosis in tumours when combined with radiotherapy. Encouragingly, toxicological and behavioural studies revealed that mubritinib is well tolerated and spares normal cells. Our findings underscore the promising therapeutic potential of mubritinib, warranting its further exploration in clinic for glioblastoma therapy.
ISSN:1757-4684

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