An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers

Genaro R. Villa, Jonathan J. Hulce, Ciro Zanca, Junfeng Bi, Shiro Ikegami, Gabrielle L. Cahill, Yuchao Gu, Kenneth M. Lum, Kenta Masui, Huijun Yang, Xin Rong, Cynthia Hong, Kristen M. Turner, Feng Liu, Gary C. Hon, David Jenkins, Michael Martini, Aaron M. Armando, Oswald Quehenberger, Timothy F. CloughesyFrank B. Furnari, Webster K. Cavenee, Peter Tontonoz, Timothy C. Gahman, Andrew K. Shiau, Benjamin F. Cravatt, Paul S. Mischel

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Small-molecule inhibitors targeting growth factor receptors have failed to show efficacy for brain cancers, potentially due to their inability to achieve sufficient drug levels in the CNS. Targeting non-oncogene tumor co-dependencies provides an alternative approach, particularly if drugs with high brain penetration can be identified. Here we demonstrate that the highly lethal brain cancer glioblastoma (GBM) is remarkably dependent on cholesterol for survival, rendering these tumors sensitive to Liver X receptor (LXR) agonist-dependent cell death. We show that LXR-623, a clinically viable, highly brain-penetrant LXRα-partial/LXRβ-full agonist selectively kills GBM cells in an LXRβ- and cholesterol-dependent fashion, causing tumor regression and prolonged survival in mouse models. Thus, a metabolic co-dependency provides a pharmacological means to kill growth factor-activated cancers in the CNS.

Original languageEnglish (US)
Pages (from-to)683-693
Number of pages11
JournalCancer Cell
Volume30
Issue number5
DOIs
StatePublished - Nov 14 2016

Keywords

  • brain cancer
  • cholesterol
  • glioblastoma
  • liver X receptor
  • metabolism
  • oxysterols

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Villa, G. R., Hulce, J. J., Zanca, C., Bi, J., Ikegami, S., Cahill, G. L., Gu, Y., Lum, K. M., Masui, K., Yang, H., Rong, X., Hong, C., Turner, K. M., Liu, F., Hon, G. C., Jenkins, D., Martini, M., Armando, A. M., Quehenberger, O., ... Mischel, P. S. (2016). An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers. Cancer Cell, 30(5), 683-693. https://doi.org/10.1016/j.ccell.2016.09.008