GSE161573
Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1a to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma [ChIP-Seq]
By integration of transcriptome, CHIP-seq, ATAC-seq, proteomic and metabolite screening followed by carbon tracing (U-13C-Glucose, U-13C-Glutamine and U-13C-Palmitic acid) and extracellular flux analysis we provided evidence that genetic (shRNA and CRISPR/Cas9) and pharmacological (Alisertib) AURKA inhibition elicited substantial metabolic reprogramming supported in part by inhibition of MYC targets and concomitant activation of PPARA signaling. While glycolysis was suppressed by AURKA inhibition, we noted a compensatory increase in oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO). Whereas interference with AURKA elicited a suppression of c-Myc, we detected an upregulation of PGC1a, a master regulator of oxidative metabolism, upon AURKA inhibition. Chromatin immunoprecipitation experiments confirmed binding of c-Myc to the promoter region of PGC1a, which is abrogated by AURKA inhibition and in turn unleashed PGC1a expression. To interfere with this oxidative metabolic reprogramming, we combined AURKA inhibitors with inhibitors of FAO (etomoxir) and electron transport chain (gamitrinib) and found substantial synergistic growth inhibition in patient derived xenograft in vitro and extension of overall survival without induction of toxicity in normal tissue. Overall design: GBM22 cells were exposed with alisertib for 10 days to generate resistance cell line (GBM22AR). Thereafter, cells were harvested and subjected to CHIP isolation. DNA was subsequently processed for CHIP sequencing.