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. Diffuse midline gliomas are lethal brain tumors, mostly affecting children. The drug Dordaviprone was recently approved by the Food and Drug Administration as the first systemic therapy for this disease. However, it is not a cure. In this study, we asked why some patients stop responding to Dordaviprone and how we might overcome this resistance. By analyzing tumor samples from patients, we found that resistant tumors increase their number of mitochondria, structures that produce energy, helping them to survive treatment. Blocking this energy-producing process enhanced Dordaviprone’s effectiveness. Moreover, Dordaviprone enhanced anti-tumor immune responses and may thus synergize with emerging immunotherapies.
Okada et al. (Sun,) studied this question.
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