Exploiting Mitochondrial Metabolic Vulnerabilities in Glioblastoma: Therapeutic Potential of Mubritinib

Exploiting Mitochondrial Metabolic Vulnerabilities in Glioblastoma Therapeutic Potential of Mubritinib

Glioblastoma remains one of the most treatment-resistant and lethal cancers, driven in part by a subset of self-renewing brain tumour stem cells (BTSCs) that contribute to therapy resistance and relapse. In a recent study, Ahmad Sharanek and his team from the University of Bordeaux and INSERM investigated the therapeutic potential of mubritinib in targeting BTSCs and glioblastoma progression by disrupting mitochondrial function.

The study demonstrated that mubritinib effectively impairs BTSC stemness and growth by targeting complex I of the electron transport chain. This disruption impairs self-renewal and proliferation, leading to a significant impact on glioblastoma progression. Gene expression profiling and Western blot analysis further revealed that mubritinib affects the AMPK/p27Kip1 pathway, resulting in cell-cycle impairment.

Importantly, pharmacokinetic assays confirmed that mubritinib crosses the blood-brain barrier, making it a viable candidate for glioblastoma therapy. Using preclinical patient-derived and syngeneic models, researchers observed that mubritinib delays tumour progression and extends survival. When combined with radiotherapy or chemotherapy, mubritinib provided an additional survival advantage.

A crucial finding was that mubritinib alleviates tumour hypoxia, enhancing reactive oxygen species (ROS) generation, DNA damage, and apoptosis when combined with radiotherapy. Toxicological and behavioural studies confirmed that mubritinib is well tolerated and spares normal cells, further supporting its potential as a therapeutic candidate.

This study highlights the promising therapeutic role of mubritinib in glioblastoma treatment by targeting mitochondrial respiration. By impairing mitochondrial function, mubritinib suppresses glioblastoma stem cells and tumour growth, while combination therapy with current standard treatments provides further therapeutic benefits. Given its well-tolerated profile and ability to penetrate the blood-brain barrier, mubritinib warrants further clinical exploration for glioblastoma therapy.

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Image Credits: Burban et al. EMBO Molecular Medicine (2025)

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