Mek/erk and ampk signaling dictate vulnerability to fatty acid desaturation inhibition in glioblastoma

Abstract Lipid metabolism is altered in many cancers. Glioma stem cells (GSCs), a subpopulation that contributes to molecular heterogeneity and therapeutic resistance of glioblastoma (GBM), are highly dependent on de novo lipid synthesis (DNLS) for energy production and proliferation. Although DNLS is a promising therapeutic target in GBM and other tumors, the molecular mechanisms that determine the dependence on DNLS remain largely unknown. In this study, we aimed to define the genetic drivers of vulnerability to DNLS inhibitors in GSCs and to explore the molecular mechanisms dictating resistance to a brain-penetrant inhibitor of stearoyl-CoA desaturase (SCD), a key enzyme involved in DNLS. Using an astrocyte model of gliomagenesis, we discovered that activation of RAS/MEK/ERK promotes vulnerability to DNLS inhibitors, whereas defective MEK/ERK activity drives resistance to SCD inhibition. Also, we identified the energy sensor AMPK as a downstream target of MEK/ERK and discovered an adaptive metabolic reprograming of GSCs dictated by AMPK activation. Shotgun lipidomics revealed that constitutive AMPK activation protects from SCD inhibition-induced lipotoxicity and endoplasmic reticulum stress and preserves the ability of transformed cells to form brain tumors in mice. Mechanistically, we found that AMPKs ability to circumvent lipotoxicity was achieved by altering the lipid composition and saturation state of cell membranes, and channeling potentially lipotoxic fatty acids into lipid droplets (i.e., lipid storage). These results strongly suggest that the efficacy of DNLS-targeted therapy can be dictated by the MEK/ERK and AMPK signaling status of GSCs. These data also suggest that MEK/ERK and AMPK signaling could be used as predictive biomarkers to understand which GBM patients are likely to respond to DNLS-targeted therapy. In conclusion, our data uncover an unexpected mechanism by which GSCs avoid a metabolic vulnerability and provides a rationale for integrating DNLS-targeted therapies for GBM treatment.