Exploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile
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/p27<sup>Kip1</sup> 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.
Authors
- Mathieu Larroquette (ORCID: https://orcid.org/0000-0001-7963-3887)
- H. Artee Luchman (ORCID: https://orcid.org/0000-0002-6663-9929)
- Joris Guyon (ORCID: https://orcid.org/0000-0001-6692-2890)
- Thomas Daubon (ORCID: https://orcid.org/0000-0002-0319-7617)
- David Cappellen (ORCID: https://orcid.org/0000-0002-9634-2595)
- Barbara Klink (ORCID: https://orcid.org/0000-0002-8753-8238)
- Benjamin Dartigues (ORCID: https://orcid.org/0000-0003-1882-123X)
- Nathalie Nicot
- Lucie Brisson
- Audrey Burban (ORCID: https://orcid.org/0009-0000-4114-0403)
- Macha Nikolski (ORCID: https://orcid.org/0000-0001-6059-577X)
- Thomas Mathivet
- Johanna Galvis (ORCID: https://orcid.org/0000-0001-9852-3798)
- Andréas Bikfalvi (ORCID: https://orcid.org/0000-0003-4138-5229)
- Samuel Weiss (ORCID: https://orcid.org/0009-0003-9190-563X)
- Ahmad Sharanek (ORCID: https://orcid.org/0000-0002-0558-3626)
- Mathis Pinglaut
- Maxime Toujas
- Cloé Tessier
- Emmanuelle Georget
- Cloe Lubiato
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université de Bordeaux (FR)
- Inserm (FR)
- University of Calgary (CA)
- University of Luxembourg (LU)
- Centre Hospitalier Universitaire de Bordeaux (FR)
- Luxembourg Institute of Health (LU)
- Bordeaux Population Health (FR)
- Institut de Biochimie et Génétique Cellulaires (FR)
- Laboratoire National de Santé (LU)
- Ontario Brain Institute (CA)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-02-03
- DOI
- https://doi.org/10.1038/s44321-025-00195-6
- Citations
- 3
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 2.81
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation ARC pour la Recherche sur le Cancer
- Fondation de France
- Institut National Du Cancer
- Advanced Remanufacturing and Technology Centre
- H2020 Marie Skłodowska-Curie Actions