An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers
Menée à l'aide de modèles murins de glioblastome, cette étude met en évidence des mécanismes de nature métabolique par lesquels le cholestérol favorise la survie des cellules cancéreuses, puis évalue l'activité antitumorale d'une petite molécule appelée LXR-623
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
α-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.
Cancer Cell 2016