Single-nucleus profiling of postmortem diffuse midline gliomas identifies mitochondrial biogenesis as a resistance mechanism to imipridone therapy

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ID: 314889
2026
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Abstract
BACKGROUND: Imipridone ONC201 is the first FDA-approved therapy for H3K27-altered diffuse midline glioma; however, clinical responses remain limited. Defining tumor-intrinsic determinants and microenvironmental, extrinsic factors that shape sensitivity or resistance to imipridones will identify actionable therapeutic opportunities and inform improved clinical strategies. METHODS: To identify mechanisms of imipridone resistance, we obtained postmortem brain tissue from DMG patients who had received imipridones and/or standard care. Single-nucleus RNA and open-chromatin sequencing were performed on N = 22 cases. Immunofluorescence-based myeloid phenotyping was performed on N = 46 cases. Mitochondrial copy-number analysis was performed on N = 19 cases. Validation of imipridone sensitivity, its effect on mitochondrial density, and its synergy with inhibition of mitochondrial biogenesis was assessed in DMG primary cells. RESULTS: We established a single-cell RNA/open-chromatin atlas from postmortem DMG cases and found imipridone treatment resulted in regressed mesenchymal transition, reduced myeloid-derived suppressive cells, and reversed aberrant H3K27-altered enhancer activity. Resistant tumors showed increased mitochondrial density, turnover, and membrane potential. Mitochondrial biogenesis and PPARGC1A emerged as resistance biomarkers and actionable targets. CONCLUSIONS: These studies implicate mitochondrial biogenesis as a biomarker of imipridone resistance and a focus for the development of combinatorial strategies to provide effective therapeutic options for a challenging pediatric brain tumor.
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Authors Masahiro Okada, Bavani Subramaniam, Baobao Geng, Jangham Jung, Bohyeon Yu, Felicia Lin, Yu Fu, Yishu Wang, Weiqiang Yu, Sandra Laternser, N. Gupta, Sabine Müller, Lin Wang, Aaron Diaz, Javad Nazarian
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Journal journal of neuro-oncology
Year 2026
DOI
10.1093/neuonc/noag119
URL
https://doi.org/10.1093/neuonc/noag119
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