Target identification reveals lanosterol synthase as a vulnerability in glioma.
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| 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.
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| Authors | 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 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 16 Pg. 7957-7962 (04 16 2019) ISSN: 1091-6490 [Electronic] United States |
| PMID | 30923116 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
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