Diffuse midline glioma is an epigenetically driven disease defined by alterations targeting the histone post-translational modification H3K27me3 resulting in epigenetic rewiring and imposing unique metabolic dependencies. ACVR1-mutations arise in ~25% of DMG H3K27-altered patients and impart a selective dependency on the kinase it encodes (ALK2), however ALK2 inhibitors show modest single-agent efficacy in vivo. In an attempt to better understand the cellular consequences of ALK2 inhibition to identify mechanistically-driven drug combinations, integrated multi-omics analysis was performed and revealed a novel role for ALK2 in cholesterol homeostasis while CRISPR and high-throughput drug screens identified hits targeting cholesterol metabolism as sensitisers to ALK2i. In vivo assessment of ALK2i plus clinically well-tolerated statins revealed a significant increase in the median survival compared to vehicle. Forced differentiation of DMG cells from an oligodendrocyte precursor-like to an astrocyte-like cell-state and led to a significant decrease in ALK2i sensitivity and synergy with statins, which was phenocopied when DMG cells were co-cultured with normal astrocytes. We identify a previously unappreciated role for ALK2 signalling in cholesterol homeostasis, showing cell-state dependency, and identify a rational combinatorial strategy for clinical translation.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 1
- Comments 0