EXTH-104. ROLE OF CLPP AND MITOCHONDRIAL METABOLISM IN THE ANTI-CANCER EFFECTS OF IMIPRIDONE ONC201 AND ONC206 IN GLIOBLASTOMA AND DIPG

Abstract ONC201 is the first bitopic dopamine receptor D2 (DRD2) antagonist and allosteric mitochondrial protease ClpP agonist. well tolerated induces durable tumor regressions in H3 K27M-mutant glioma patients. ONC206, a derivative of currently Phase I trials, also DRD2 agonist with enhanced nanomolar potency relative to ONC201. We evaluated vitro efficacy, mechanism(s) action acquired resistance for ONC206 glioblastoma (GBM) (T98G, A172, U87MG), H3.3 K27M mutant DIPG (SF8628, SF7761) astrocytoma (H4, U118MG) cell lines. was more potent than viability assays all line. A mutation has previously been associated imipridones. Accordingly, SF8628 cells CRISPR-mediated knockout were resistant both ONC206. Polyclonal lines generated through prolonged passaging increasing concentrations (SF8628 T98G cells) or (T98G cells). Cells (ONC201Res) (ONC206Res) showed cross Time-stability confirmed by removing drug 2 4 weeks retesting. Whole genome sequencing revealed mutations ONC201Res ONC206Res cells. RNAseq analysis upregulation integrated stress response, apoptosis pathways, amino acid metabolism imipridone treatment parental but not clones. Depleting glucose media inhibition imipridones, indicating may contribute their mechanism action. Our results identify as key aspects ON206 GBM