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

dc.rights.licenseopenen_US
dc.contributor.authorBURBAN, Audrey
dc.contributor.authorTESSIER, Cloe
dc.contributor.authorLARROQUETTE, Mathieu
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorGUYON, Joris
dc.contributor.authorLUBIATO, Cloe
dc.contributor.authorPINGLAUT, Mathis
dc.contributor.authorTOUJAS, Maxime
dc.contributor.authorGALVIS, Johanna
dc.contributor.authorDARTIGUES, Benjamin
dc.contributor.authorGEORGET, Emmanuelle
dc.contributor.authorLUCHMAN, H Artee
dc.contributor.authorWEISS, Samuel
dc.contributor.authorCAPPELLEN, David
dc.contributor.authorNICOT, Nathalie
dc.contributor.authorKLINK, Barbara
dc.contributor.authorNIKOLSKI, Macha
IDREF: 134506049
dc.contributor.authorBRISSON, Lucie
dc.contributor.authorMATHIVET, Thomas
dc.contributor.authorBIKFALVI, Andreas
dc.contributor.authorDAUBON, Thomas
dc.contributor.authorSHARANEK, Ahmad
dc.date.accessioned2025-04-10T15:35:19Z
dc.date.available2025-04-10T15:35:19Z
dc.date.issued2025-02-03
dc.identifier.issn1757-4676en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/206103
dc.description.abstractEnGlioblastoma 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.isoENen_US
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.subject.enHypoxia
dc.subject.enMetabolic Reliance
dc.subject.enOxidative Phosphorylation
dc.subject.enRadiotherapy
dc.subject.enReactive Oxygen Species.
dc.title.enExploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile
dc.title.alternativeEMBO Mol Meden_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1038/s44321-025-00195-6en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed39901019en_US
bordeaux.journalEMBO Molecular Medicineen_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.teamAHEAD_BPHen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.identifier.funderIDFondation de Franceen_US
bordeaux.identifier.funderIDInstitut National Du Canceren_US
hal.identifierhal-05029807
hal.version1
hal.date.transferred2025-04-10T15:35:24Z
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exporttrue
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_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


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