TY - JOUR
T1 - Target identification reveals lanosterol synthase as a vulnerability in glioma
AU - Phillips, Richard E.
AU - Yang, Yanhong
AU - Smith, Ryan C.
AU - Thompson, Bonne M.
AU - Yamasaki, Tomoko
AU - Soto-Feliciano, Yadira M.
AU - Funato, Kosuke
AU - Liang, Yupu
AU - Garcia-Bermudez, Javier
AU - Wang, Xiaoshi
AU - Garcia, Benjamin A.
AU - Yamasaki, Kazuhiko
AU - McDonald, Jeffrey G.
AU - Birsoy, Kivanç
AU - Tabar, Viviane
AU - Allis, C. David
N1 - Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/4/16
Y1 - 2019/4/16
N2 - 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.
AB - 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.
KW - Glioma
KW - Lanosterol synthase
KW - MI-2
KW - Menin inhibitor
KW - Target identification
UR - http://www.scopus.com/inward/record.url?scp=85064416785&partnerID=8YFLogxK
U2 - 10.1073/pnas.1820989116
DO - 10.1073/pnas.1820989116
M3 - Article
C2 - 30923116
AN - SCOPUS:85064416785
SN - 0027-8424
VL - 116
SP - 7957
EP - 7962
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 16
ER -