Target identification reveals lanosterol synthase as a vulnerability in glioma
Menée sur des lignées cellulaires de gliomes infiltrants du tronc cérébral et de gliomes provenant de patients adultes, cette étude démontre que la lanostérol synthase, une enzyme métabolique impliquée dans l'homéostasie du cholestérol, est une cible thérapeutique de l'inhibiteur de la ménine MI-2
Diffuse intrinsic pontine glioma (DIPG) is an incurable childhood cancer with a median survival of less than 1 y. Characterization of druggable targets in this disease remains a longstanding goal, as no pharmacological agents have proven efficacy in this malignancy. We recently identified the menin inhibitor, MI-2, as exhibiting potent antitumor activity in preclinical models of DIPG. Here, we show that MI-2 exerts its activity in glioma largely independent of its ability to target the epigenetic regulator menin, but instead by disrupting cholesterol homeostasis through direct inhibition of the cholesterol biosynthesis enzyme, lanosterol synthase, revealing this metabolic enzyme as an actionable vulnerability in glioma and implicating cholesterol homeostasis as an attractive pathway to target in malignant gliomas.Diffuse intrinsic pontine glioma (DIPG) remains an incurable childhood brain tumor for which novel therapeutic approaches are desperately needed. Previous studies have shown that the menin inhibitor MI-2 exhibits promising activity in preclinical DIPG and adult glioma models, although the mechanism underlying this activity is unknown. Here, using an integrated approach, we show that MI-2 exerts its antitumor activity in glioma largely independent of its ability to target menin. Instead, we demonstrate that MI-2 activity in glioma is mediated by disruption of cholesterol homeostasis, with suppression of cholesterol synthesis and generation of the endogenous liver X receptor ligand, 24,25-epoxycholesterol, resulting in cholesterol depletion and cell death. Notably, this mechanism is responsible for MI-2 activity in both DIPG and adult glioma cells. Metabolomic and biochemical analyses identify lanosterol synthase as the direct molecular target of MI-2, revealing this metabolic enzyme as a vulnerability in glioma and further implicating cholesterol homeostasis as an attractive pathway to target in this malignancy.