A hallmark of cellular transformation is the evasion of contact-dependent inhibition of growth. To find new therapeutic targets for glioblastoma, we looked for pathways that are inhibited by high cell density in normal astrocytes but have lost this regulation in glioma cells. Here we report that at high cell density, normal astrocytes turn off cholesterol synthesis but glioma cells keep this pathway on. Correspondingly, cholesterol pathway upregulation is associated with poor prognosis in glioblastoma patients. Densely-plated glioma cells increase oxygen consumption to synthesize cholesterol, resulting in a decrease in reactive oxygen species, TCA cycle intermediates, and ATP, but without a compensating increase in aerobic glycolysis. This constitutive cholesterol synthesis is controlled by the cell cycle, as it can be turned off by cyclin dependent kinase inhibitors and it correlates with disabled cell cycle control though loss of p53 and RB. Finally, glioma cells, but not astrocytes, are sensitive to cholesterol synthesis inhibition downstream of the mevalonate pathway, suggesting that specifically targeting cholesterol synthesis might be an effective treatment for glioblastoma.

Citation Format: Diane M. Kambach, Alan S. Halim, A. Gesine Cauer, Qian Sun, Carlos A. Tristan, Orieta Celiku, Aparna H. Kesarwala, Uma Shankavaram, Eric Batchelor, Jayne M. Stommel. Dysregulated cholesterol synthesis is a therapeutic vulnerability in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3116. doi:10.1158/1538-7445.AM2017-3116