Oncogenic mutations in growth factor receptor signaling pathways are common in cancer, including in tumors that arise from or metastasize to the brain. However, most small-molecule inhibitors targeting growth factor receptors have failed to show efficacy for brain cancers, potentially due to inability to achieve sufficient drug levels in the central nervous system (CNS). Targeting tumor co-dependencies provides an alternative approach, particularly if drugs with high brain penetration can be identified.
In vitro cytotoxicity assays, mass spectoscopy, and orthotopic GBM in vivo models were used to assess cholesterol dependency and sensitivity to Liver X Receptor (LXR) activation using established GBM cell lines and patient-derived ex vivo tumor neurosphere cultures.
We demonstrate that EGFR-mutant cancers, including a highly lethal form of brain cancer glioblastoma (GBM), are remarkably dependent on cholesterol for survival, rendering them 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 significant 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.
Ludwig Institute for Cancer Research
National Institute of Health, National Cancer Institute, F31CA186668
The author has declared no conflicts of interest.