Target identification reveals lanosterol synthase as a vulnerability in glioma

Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7957-7962. doi: 10.1073/pnas.1820989116. Epub 2019 Mar 28.

Abstract

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.

Keywords: MI-2; glioma; lanosterol synthase; menin inhibitor; target identification.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Brain Stem Neoplasms* / enzymology
  • Brain Stem Neoplasms* / metabolism
  • Cholesterol / metabolism
  • Glioma* / enzymology
  • Glioma* / metabolism
  • Humans
  • Intramolecular Transferases / metabolism*
  • Metabolic Networks and Pathways / drug effects
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism

Substances

  • Antineoplastic Agents
  • MEN1 protein, human
  • Proto-Oncogene Proteins
  • Cholesterol
  • Intramolecular Transferases
  • lanosterol synthase