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 - Funding Information:
ACKNOWLEDGMENTS. We thank members of the C.D.A. laboratory for their feedback regarding this work and Dr. Tarun Kapoor of Rockefeller University and Dr. David Russell of University of Texas Southwestern Medical Center for invaluable discussions regarding the project. We thank Mr. O. Tani of National Institute of Advanced Industrial Science and Technology for helpful advice regarding the NMR biochemical assay. We thank Dr. M. Monje of Stanford University and Dr. A. Carcabosa of Hospital Sant Joan De Deu for DIPG cell-lines used in this work. This work was made possible by funding from NIH Grant P01CA196539 (to C.D.A. and B.A.G.). V.T. is supported by National Cancer Institute Grant R01CA3865730 and Starr Cancer Consortium. J.G.M. is supported in part by NIH Grant HL20948. B.A.G. is supported by NIH Grants CA196539, GM110104 and a Leukemia and Lymphoma Society Robert Arceci Scholar Award. R.E.P. is supported by the American Brain Tumor Association Basic Research Fellowship in honor of Bruce and Brian Jackson, Memorial Sloan Kettering Internal Diversity Enhancement Award, Cure Childhood Cancer, and the Cure Starts Now.
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 -