Co-targeting neurotransmitter signaling and CDK9 to treat diffuse midline glioma [CUT&RUN]

In this study, we uncover mechanisms of crosstalk between monoamine neurotransmitter signaling and transcriptional regulation in diffuse midline glioma (DMG) that can be co-targeted with CDK9 inhibitors (CDK9i) and neuropsychiatric drugs as a potential treatment strategy for DMG. We identified compounds that synergize with CDK9i in DMG using targeted drug screens, then assessed DMG response to CDK9i and neurotransmitter-targeting drugs in cell culture and in orthotopic xenograft mouse models.

We then used a multi-omic approach combining proteomic, transcriptomic, and chromatin profiling with phospho-proteomics, RNA-seq, CUT&RUN, and ATAC-seq in DMG cells to characterize mechanisms of synergy between CDK9i and neuropsychiatric drugs. We observe differential expression of neuronal signaling genes in both CDK9i-resistant DMG xenograft tumors and CDK9-low pediatric high grade glioma patient tumors. Additional studies reveal that drugs that modify monoamine neurotransmitter signaling, including neurotransmitter reuptake inhibitors (SSRI/SNRI) and both metabotropic neurotransmitter receptor agonists and antagonists, strongly synergize with CDK9i to reduce DMG cell viability.