Aurora kinase A inhibition reverses the Warburg effect and elicits unique metabolic vulnerabilities in glioblastoma

Trang T T Nguyen,Enyuan Shang,Jeffrey N Bruce,Guoan Zhang,Peter Canoll,Hee Won Yang,Markus D Siegelin,Angeliki Mela,Hasan Orhan Akman,Chang Shu,Sungsoo Kim,Nelson Humala,Mike-Andrew Westhoff,Georg Karpel-Massler,Aayushi Mahajan,Catarina M Quinzii

doi:10.1038/s41467-021-25501-x

Abstract

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.

Highlights

Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM)
Silencing of c-Myc resulted in a significant reduction of the effect of AURKA inhibition on cellular viability in SF188 and GBM22 cells (Fig. 1d), suggesting that c-Myc is a key mediator in this context
Whereas Aurora kinase A inhibition resulted in suppression of glycolysis, it concomitantly activated oxidative metabolism, suggesting that metabolic reprogramming might represent an escape mechanism of GBM cells from therapy

Summary

Introduction

Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). resistance to therapy remains a critical issue. 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. Aurora kinases are important for the proliferation and growth of solid tumors, including glioblastomas They are phosphorylating several substrates that are directly involved in cell cycle regulation. In a manner dependent on the transcription factors c-MYC and PGC1α treatment with Aurora kinase A inhibitors renders GBM cells highly oxidative and dependent on fatty acid oxidation that in turn mediates them to be susceptible to inhibitors of FAO in vitro and in vivo

Methods

Results

Conclusion