Exploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile
| dc.rights.license | open | en_US |
| dc.contributor.author | BURBAN, Audrey | |
| dc.contributor.author | TESSIER, Cloe | |
| dc.contributor.author | LARROQUETTE, Mathieu | |
| hal.structure.identifier | Bordeaux population health [BPH] | |
| dc.contributor.author | GUYON, Joris | |
| dc.contributor.author | LUBIATO, Cloe | |
| dc.contributor.author | PINGLAUT, Mathis | |
| dc.contributor.author | TOUJAS, Maxime | |
| dc.contributor.author | GALVIS, Johanna | |
| dc.contributor.author | DARTIGUES, Benjamin | |
| dc.contributor.author | GEORGET, Emmanuelle | |
| dc.contributor.author | LUCHMAN, H Artee | |
| dc.contributor.author | WEISS, Samuel | |
| dc.contributor.author | CAPPELLEN, David | |
| dc.contributor.author | NICOT, Nathalie | |
| dc.contributor.author | KLINK, Barbara | |
| dc.contributor.author | NIKOLSKI, Macha | |
| dc.contributor.author | BRISSON, Lucie | |
| dc.contributor.author | MATHIVET, Thomas | |
| dc.contributor.author | BIKFALVI, Andreas | |
| dc.contributor.author | DAUBON, Thomas | |
| dc.contributor.author | SHARANEK, Ahmad | |
| dc.date.accessioned | 2025-04-10T15:35:19Z | |
| dc.date.available | 2025-04-10T15:35:19Z | |
| dc.date.issued | 2025-02-03 | |
| dc.identifier.issn | 1757-4676 | en_US |
| dc.identifier.uri | https://oskar-bordeaux.fr/handle/20.500.12278/206103 | |
| dc.description.abstractEn | 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(Kip1) 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. | |
| dc.language.iso | EN | en_US |
| dc.rights | Attribution 3.0 United States | * |
| dc.rights.uri | http://creativecommons.org/licenses/by/3.0/us/ | * |
| dc.subject.en | Hypoxia | |
| dc.subject.en | Metabolic Reliance | |
| dc.subject.en | Oxidative Phosphorylation | |
| dc.subject.en | Radiotherapy | |
| dc.subject.en | Reactive Oxygen Species. | |
| dc.title.en | Exploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile | |
| dc.title.alternative | EMBO Mol Med | en_US |
| dc.type | Article de revue | en_US |
| dc.identifier.doi | 10.1038/s44321-025-00195-6 | en_US |
| dc.subject.hal | Sciences du Vivant [q-bio]/Santé publique et épidémiologie | en_US |
| dc.identifier.pubmed | 39901019 | en_US |
| bordeaux.journal | EMBO Molecular Medicine | en_US |
| bordeaux.hal.laboratories | Bordeaux Population Health Research Center (BPH) - UMR 1219 | en_US |
| bordeaux.institution | Université de Bordeaux | en_US |
| bordeaux.institution | INSERM | en_US |
| bordeaux.team | AHEAD_BPH | en_US |
| bordeaux.peerReviewed | oui | en_US |
| bordeaux.inpress | non | en_US |
| bordeaux.identifier.funderID | Fondation de France | en_US |
| bordeaux.identifier.funderID | Institut National Du Cancer | en_US |
| hal.identifier | hal-05029807 | |
| hal.version | 1 | |
| hal.date.transferred | 2025-04-10T15:35:24Z | |
| hal.popular | non | en_US |
| hal.audience | Internationale | en_US |
| hal.export | true | |
| dc.rights.cc | Pas de Licence CC | en_US |
| bordeaux.COinS | ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=EMBO%20Molecular%20Medicine&rft.date=2025-02-03&rft.eissn=1757-4676&rft.issn=1757-4676&rft.au=BURBAN,%20Audrey&TESSIER,%20Cloe&LARROQUETTE,%20Mathieu&GUYON,%20Joris&LUBIATO,%20Cloe&rft.genre=article |