TY - JOUR T1 - Divergent MEK/ERK and AMPK signaling dictate lipogenic plasticity and dependence on fatty acid synthesis in Glioblastoma JF - bioRxiv DO - 10.1101/2022.04.07.487530 SP - 2022.04.07.487530 AU - Katharina M. Eyme AU - Alessandro Sammarco AU - Roshani Jha AU - Hayk Mnatsakanyan AU - Rudolph Neustadt AU - Charlotte Moses AU - Ahmad Alnasser AU - Daniel Tardiff AU - Baolong Su AU - Kevin J Williams AU - Steven J. Bensinger AU - Chee Yeun Chung AU - Christian E. Badr Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/04/08/2022.04.07.487530.1.abstract N2 - Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in Glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-targeted therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage, brain-penetrant inhibitor of stearoyl CoA desaturase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desaturation in GSCs orthotopically implanted in mice. When administered as a single agent, or particularly in combination with the first line GBM chemotherapy, Temozolomide (TMZ), YTX-7739 showed therapeutic efficacy in orthotopic GSC mouse models owing to its lipotoxicity and its ability to impair DNA damage repair. Leveraging genetic, pharmacological, and physiological manipulation of key signaling nodes in gliomagenesis, we uncover that aberrant MEK/ERK signaling and its repression of the energy sensor AMP-activated protein kinase (AMPK) primarily drives therapeutic vulnerability to SCD and other DNLS inhibitors. Conversely, AMPK activation mitigates lipotoxicity and renders GSCs impervious to the loss of DNLS, both in culture and in vivo, by decreasing the saturation state of phospholipids and diverting toxic lipids into lipid droplets. Altogether, our findings reveal mechanisms of metabolic plasticity in GSCs and provide a framework for rational integration of DNLS-targeted therapies for the treatment of GBM.Competing Interest StatementDFT and CYC are past or current employees of Yumanity Therapeutics. CEB received in-kind support from Yumanity Therapeutics. ER -