AURKA Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

We described the metabolic alterations in glioblastoma model systems elicited by AURKA inhibition. By utilizing proteomic and transcriptomic analyses coupled with untargeted polar and nonpolar metabolite analysis by LC/MC, we found that AURKA inhibition leads to a profound reprogramming of tumor metabolism, which suppresses c-Myc protein levels and increases pro-survival PGC1α which in concert mediate a suppression of glycolysis and a concomitant activation of oxidative phosphorylation (OXPHOS) that is fueled by enhanced fatty acid oxidation (FAO). We targeted these metabolic aberrations with novel combination therapies involving clinical approved drugs in glioblastoma system both in vitro and in vivo. We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated and down-regulated genes in Alisertib resistant cells. GBM22 cells were chronically treated with Alisertib for 10 days. Then the cells were collected and mRNA was extracted.