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Target Identification Reveals Lanosterol Synthase as a Vulnerability in Glioma

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, etc.

Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7957-7962.

PMID: 30923116

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP79630	Lanosterol		79-63-0	Price

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