期刊
CANCER CELL
卷 30, 期 5, 页码 683-693出版社
CELL PRESS
DOI: 10.1016/j.ccell.2016.09.008
关键词
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资金
- National Cancer Institute [F31CA186668]
- National Institute for Neurological Diseases and Stroke [NS73831, NS080939]
- Defeat GBM Program of the National Brain Tumor Society
- Ben and Catherine Ivy Foundation
- NIH [CA132630]
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 LXR alpha-partial/LXR beta-full agonist selectively kills GBM cells in an LXR beta- 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.
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