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

Trang T. T. Nguyen, Enyuan Shang, Chang Shu, Sungsoo Kim, Angeliki Mela, Nelson Humala, Aayushi Mahajan, Hee Won Yang, Hasan Orhan Akman, Catarina M. Quinzii, Guoan Zhang, Mike-Andrew Westhoff, Georg Karpel-Massler, Jeffrey N. Bruce, Peter Canoll and Markus D. Siegelin ()
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Trang T. T. Nguyen: Columbia University Medical Center
Enyuan Shang: City University of New York, Bronx
Chang Shu: Columbia University Medical Center
Sungsoo Kim: Columbia University Medical Center
Angeliki Mela: Columbia University Medical Center
Nelson Humala: Columbia University Medical Center
Aayushi Mahajan: Columbia University Medical Center
Hee Won Yang: Columbia University Medical Center
Hasan Orhan Akman: Columbia University Medical Center
Catarina M. Quinzii: Columbia University Medical Center
Guoan Zhang: Weill Cornell Medicine
Mike-Andrew Westhoff: Ulm University Medical Center
Georg Karpel-Massler: Ulm University Medical Center
Jeffrey N. Bruce: Columbia University Medical Center
Peter Canoll: Columbia University Medical Center
Markus D. Siegelin: Columbia University Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25501-x

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