Burban Audrey, Tessier Cloe, Larroquette Mathieu, Guyon Joris, Lubiato Cloe, Pinglaut Mathis, Toujas Maxime, Galvis Johanna, Dartigues Benjamin, Georget Emmanuelle, Luchman H Artee, Weiss Samuel, Cappellen David, Nicot Nathalie, Klink Barbara, Nikolski Macha, Brisson Lucie, Mathivet Thomas, Bikfalvi Andreas, Daubon Thomas, Sharanek Ahmad
University of Bordeaux, CNRS, IBGC, UMR5095, Bordeaux, France.
University of Bordeaux, INSERM, UMR1312, BRIC, BoRdeaux Institute of onCology, Bordeaux, France.
EMBO Mol Med. 2025 Mar;17(3):469-503. doi: 10.1038/s44321-025-00195-6. Epub 2025 Feb 3.
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 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.
胶质母细胞瘤是最具治疗抵抗性和致命性的癌症之一，其中一部分自我更新的脑肿瘤干细胞（BTSCs）会导致治疗抵抗和复发。在此，我们报告mubritinib能有效损害BTSC的干性和生长。从机制上讲，生物能量测定和挽救实验表明，mubritinib靶向电子传递链的复合体I，从而损害BTSC的自我更新和增殖。基因表达谱分析和蛋白质印迹分析显示，mubritinib破坏AMPK/p27通路，导致细胞周期受损。通过体内药代动力学测定，我们证实mubritinib可穿过血脑屏障。使用临床前患者来源和同基因模型，我们证明mubritinib可延缓胶质母细胞瘤进展并延长动物生存期。此外，将mubritinib与放疗或化疗联合使用可为动物提供生存优势。值得注意的是，我们发现mubritinib可减轻缺氧，从而在与放疗联合使用时增强肿瘤中的ROS生成、DNA损伤和细胞凋亡。令人鼓舞的是，毒理学和行为学研究表明mubritinib耐受性良好且对正常细胞无损害。我们的研究结果强调了mubritinib有前景的治疗潜力，值得在临床上进一步探索其用于胶质母细胞瘤治疗的可能性。
