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Pharmacological induction of mitochondrial stress counteracts therapy resistance in glioblastoma stem-like cells

Miki, K.; Ghoche, M. T.; Yuan, F.; Li, F.; Manoj, N.; Oken, S.; Yoshimoto, K.; Zinn, P. O.; Agnihotri, S.; McBrayer, S. K.; Abdullah, K. G.

2026-02-09 cancer biology
10.64898/2026.02.05.704021 bioRxiv
Show abstract

Glioblastoma (GBM) stem-like cells (GSCs) contribute to therapeutic resistance and recurrence. We sought to define cellular processes underlying GSC resilience. We discovered that GSCs, unlike differentiated GBM cells (DGCs) or non-malignant neural cells, depend on mitochondrial function for survival. To target this vulnerability, we exploited doxycycline (DOXY), an antibiotic used in humans, to interfere with mitochondrial protein translation. DOXY induced cell death and inhibited sphere formation in GSCs, but not in DGCs or non-malignant cells, indicating a differentiation state-selective effect. Mechanistically, DOXY induced mitochondrial dysfunction and activated a stress-responsive apoptotic program involving HRI-mediated signaling. DOXY displayed antitumor efficacy in patient-derived GBM organoid and orthotopic xenograft models. Our study reveals that DOXY can selectively target undifferentiated glioma cells, informing a drug repurposing-based strategy.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.