Target identification reveals lanosterol synthase as a vulnerability in glioma

Richard E. Phillips, Yanhong Yang, Ryan C. Smith, Bonne M. Thompson, Tomoko Yamasaki, Yadira M. Soto-Feliciano, Kosuke Funato, Yupu Liang, Javier Garcia-Bermudez, Xiaoshi Wang, Benjamin A. Garcia, Kazuhiko Yamasaki, Jeffrey G McDonald, Kivanç Birsoy, Viviane Tabar, C. David Allis

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7957-7962
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number16
DOIs
StatePublished - Apr 16 2019

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Keywords

  • Glioma
  • Lanosterol synthase
  • Menin inhibitor
  • MI-2
  • Target identification

ASJC Scopus subject areas

  • General

Cite this

Phillips, R. E., Yang, Y., Smith, R. C., Thompson, B. M., Yamasaki, T., Soto-Feliciano, Y. M., Funato, K., Liang, Y., Garcia-Bermudez, J., Wang, X., Garcia, B. A., Yamasaki, K., McDonald, J. G., Birsoy, K., Tabar, V., & Allis, C. D. (2019). Target identification reveals lanosterol synthase as a vulnerability in glioma. Proceedings of the National Academy of Sciences of the United States of America, 116(16), 7957-7962. https://doi.org/10.1073/pnas.1820989116