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ONC201 is a promising anti-cancer agent that kills tumor cells by triggering an integrated stress response (ISR) dependent on ATF4. ONC201 demonstrated tumor regression and prolonged disease stability in patients with histone H3K27M-mutated midline glioma. The Enhancer of Zeste Homolog 2 (EZH2), a subunit of the polycomb repressive complex 2 (PRC2), is a histone methyltransferase that tri-methylates H3K27 (H3K27me3) and silences target genes. EZH2 inhibitors (EZH2i) reduce global H3K27 methylation. Based on the fact that the H3K27 mutation reduces H3K27 dimethylation (H3K27me2) and trimethylation (H3K27me3), we hypothesized that ONC201 sensitivity and tumor cell death may be enhanced by reducing H3K27 methylation with EZH2i as a mimic of H3K27M-mutation and by increasing H3K27 acetylation with histone deacetylase inhibitors (HDACi). We evaluated synergy of EZH2i EPZ-6438 or HDACi vorinostat with ONC201 against GBM cell lines, U251 and T98G-1 and DMG cell line, SF8638. Cell viability was determined with the Cell Titer Glo assay. Apoptosis was evaluated through immunoblotting of cleaved PARP and flow cytometry analysis of cell distribution. ISR activity was evaluated using immunoblotting of ATF4. Our result demonstrate that ONC201 synergistically reduced cell viability with vorinostat in U251, T98G-1 and SF8628 cell lines, induced apoptosis in combination with vorinostat in U251 and SF8628. ONC201 synergistically reduced cell viability and induced apoptosis with EPZ-6438 in U251. The immunoblotting detected no enhancement of ATF4 by addition of EPZ-6438 to ONC201. Immunoblotting analysis showed that EPZ-6438 reduced H3K27me3 in U251. Our results unravel potent synergy between ONC201 and EZH2i or HDACi in GBM and DMG cell lines, and provide further insights into the role of H3K27me3 in ONC201 drug sensitivity.

neuro-oncology

DDRE-16. SYNERGISTIC TUMOR SUPPRESSION FROM COMBINATION OF ONC201 AND EPIGENETIC MODULATORS EZH2 OR HDAC INHIBITOR PROVIDES A NOVEL TREATMENT STRATEGY FOR GBM AND DMG