CSIG-26. TARGETING EPIGENETIC DYSREGULATION AND ADAPTIVE RESISTANCE MECHANISMS IN DIPG/DMG

Abstract Diffuse intrinsic pontine gliomas (DIPG/DMG) are devastating pediatric brain tumors with very limited treatment options and a uniformly fatal prognosis. The recurrent histone H3K27M mutation in DIPG disrupts epigenetic regulation, leading to the hypothesis that this mutation-induced dysregulation creates a vulnerability to epigenetic targeting. We conducted a screening of compounds targeting epigenetic enzymes to identify potential inhibitors of patient-derived DIPG cell growth. High-throughput screening identified chaetocin, a fungal metabolite, as a potent inhibitor of DIPG cell growth. Chaetocin treatment selectively decreased proliferation and increased apoptosis in DIPG cells, significantly extending survival in DIPG xenograft models while restoring H3K27me3 levels. The loss of the H3K9 methyltransferase SUV39H1 also inhibited DIPG cell growth. Transcriptomic and epigenomic profiling showed that SUV39H1 loss or inhibition downregulated stemness and oncogenic networks, including growth factor receptor signaling. However, D2 dopamine receptor (DRD2) signaling adaptively upregulated, conferring resistance. Combining chaetocin with the DRD2 antagonist ONC201 or radiotherapy synergistically enhanced antitumor efficacy. This study reveals a therapeutic vulnerability in DIPG cells by targeting the SUV39H1-H3K9me3 pathway and compensatory signaling loops. Combining SUV39H1-targeting chaetocin with other agents, such as ONC201, may offer a new strategy for effective DIPG treatment. The findings suggest that chaetocin, by targeting and suppressing the H3K9me3 methyltransferase SUV39H1, inhibits DIPG tumor growth by downregulating stemness-related genes and growth factor signaling pathways. Overall, the study highlights a new therapeutic vulnerability in DIPG through the SUV39H1-H3K9me3 epigenetic pathway and compensatory signaling loops, suggesting an effective treatment strategy for DIPG.