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MET Inhibition Elicits PGC1α Dependent Metabolic Reprogramming in Glioblastoma

ABSTRACT: By utilizing proteomic and transcriptomic analysis coupled with untargeted polar and non-polar metabolite analysis by liquid chromatography/mass spectrometry, we identified a specific metabolic program elicited by c-MET inhibition. Interference with c-MET drives oxidative metabolism by increasing fatty acid oxidation (FAO) and glucose anaplerosis, which was orchestrated by the master-regulator, PGC1α. Based on a drug screen, we further found that the mitochondrial matrix chaperone inhibitor, gamitrinib, along with c-MET inhibition causes synergistic cell death, which was mechanistically related to the ability of gamitrinib to suppress oxidative metabolism. In alignment with these findings, FAO inhibitor, etomoxir, enhanced the anti-proliferative effects of c-MET inhibition as well. Both combination therapies were active in vivo, suggesting two novel potential combination therapies, involving c-MET inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE134676 | GEO | 2020/07/22

REPOSITORIES: GEO

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| PRJNA556029 | ENA

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