Statins and PDGFRA Inhibition: A Synergistic Strategy Against Diffuse Midline Glioma

Abstract

Diffuse midline glioma (DMG) is a fatal pediatric brain tumor with limited treatment options. While PDGFRA inhibitors, like avapritinib, have shown some promise in the clinic, DMGs have been shown to develop resistance to treatment through metabolic adaptations, including increased fatty acid synthesis and oxidative phosphorylation (OXPHOS). This study explores the metabolic basis of DMG treatment resistance to avapritinib and seeks to identify novel drugs that could synergize with avapritinib to provide a durable treatment effect. We demonstrate that atorvastatin synergizes with avapritinib, enhancing cytotoxicity in DMG cells by disrupting lipid metabolism, subsequently leading to increased apoptosis. Furthermore, we reveal that DMG cells treated with long-term avapritinib, called avapritinib-persister cells, exhibit a heightened dependency on OXPHOS and are subsequently more susceptible to statin therapy. Our findings highlight that metabolic reprogramming is a key driver of DMG treatment escape and supports the further consideration of statins as potential metabolic inhibitors when treating DMG with PDGFRA-targeted therapy. Given their established safety and widespread usage, repurposing statins in combination therapy for DMG warrants further preclinical investigation to determine if this approach improves outcomes for DMG patients.