Target identification reveals lanosterol synthase as a vulnerability in glioma Journal Article
| Authors: | 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. |
| Article Title: | Target identification reveals lanosterol synthase as a vulnerability in glioma |
| 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. © 2019 National Academy of Sciences. All rights reserved. |
| Keywords: | glioma; target identification; lanosterol synthase; menin inhibitor; mi-2 |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 116 |
| Issue: | 16 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2019-04-16 |
| Start Page: | 7957 |
| End Page: | 7962 |
| Language: | English |
| DOI: | 10.1073/pnas.1820989116 |
| PUBMED: | 30923116 |
| PROVIDER: | scopus |
| PMCID: | PMC6475387 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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