Target identification reveals lanosterol synthase as a vulnerability in glioma

Significance 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.