Single-nucleus profiling of postmortem diffuse midline gliomas identifies mitochondrial biogenesis as a resistance mechanism to imipridone therapy - PubMed
4 hours ago
- #diffuse midline glioma
- #mitochondrial biogenesis
- #imipridone resistance
- Imipridone ONC201 (Dordaviprone) is the first FDA-approved therapy for H3K27-altered diffuse midline glioma (DMG), but clinical responses are limited.
- Single-nucleus RNA and open-chromatin sequencing of postmortem DMG tissues revealed that imipridone treatment reduces mesenchymal transition, myeloid-derived suppressive cells, and aberrant H3K27-altered enhancer activity.
- Resistant tumors show increased mitochondrial density, turnover, and membrane potential, with mitochondrial biogenesis and PPARGC1A identified as key resistance biomarkers.
- Inhibition of mitochondrial biogenesis synergizes with imipridones to enhance therapeutic effectiveness in DMG primary cells.
- The study suggests combinatorial strategies targeting mitochondrial biogenesis to overcome resistance and improve outcomes for this pediatric brain tumor.