Aurora kinase A inhibition reverses the Warburg effect and elicits unique metabolic vulnerabilities in glioblastoma.
Trang T T NguyenEnyuan ShangChang ShuSungsoo KimAngeliki MelaNelson HumalaAayushi MahajanHee Won YangHasan Orhan AkmanCatarina M QuinziiGuoan ZhangMike-Andrew WesthoffGeorg Karpel-MasslerJeffrey N BrucePeter CanollMarkus D SiegelinPublished in: Nature communications (2021)
Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). However, resistance to therapy remains a critical issue. By integration of transcriptome, chromatin immunoprecipitation sequencing (CHIP-seq), Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), proteomic and metabolite screening followed by carbon tracing and extracellular flux analyses we show that genetic and pharmacological AURKA inhibition elicits metabolic reprogramming mediated by inhibition of MYC targets and concomitant activation of Peroxisome Proliferator Activated Receptor Alpha (PPARA) signaling. While glycolysis is suppressed by AURKA inhibition, we note an increase in the oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO), which was accompanied by an increase of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Combining AURKA inhibitors with inhibitors of FAO extends overall survival in orthotopic GBM PDX models. Taken together, these data suggest that simultaneous targeting of oxidative metabolism and AURKAi might be a potential novel therapy against recalcitrant malignancies.
Keyphrases
- genome wide
- single cell
- rna seq
- gene expression
- transcription factor
- fatty acid
- high throughput
- dna damage
- dna methylation
- skeletal muscle
- emergency department
- protein kinase
- stem cells
- big data
- copy number
- electronic health record
- climate change
- drug delivery
- hydrogen peroxide
- deep learning
- circulating tumor cells
- smoking cessation
- binding protein
- free survival