Metabolomics reveals tepotinib-related mitochondrial dysfunction in MET activating mutations-driven models.

Poliaková, Michaela; Felser, Andrea; Pierzchala, Katarzyna; Nuoffer, Jean-Marc; Aebersold, Daniel; Zimmer, Yitzhak; Zamboni, Nicola; Medova, Michaela (2019). Metabolomics reveals tepotinib-related mitochondrial dysfunction in MET activating mutations-driven models. FEBS journal, 286(14), pp. 2692-2710. Wiley-Blackwell 10.1111/febs.14852

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Genetic aberrations in the hepatocyte growth factor receptor tyrosine kinase MET induce oncogenic addiction in various types of human cancers, advocating MET as a viable anticancer target. Here, we report that MET signaling plays an important role in conferring a unique metabolic phenotype to cellular models expressing MET-activating mutated variants that are either sensitive or resistant towards MET small molecule inhibitors. MET phosphorylation downregulated by the specific MET inhibitor tepotinib resulted in markedly decreased viability and increased apoptosis in tepotinib-sensitive cells. Moreover, prior to the induction of MET inhibition-dependent cell death, tepotinib also led to an altered metabolic signature, characterized by a prominent reduction of metabolite ions related to amino sugar metabolism, gluconeogenesis, glycine and serine metabolism and of numerous TCA cycle-related metabolites such as succinate, malate and citrate. Functionally, a decrease in oxygen consumption rate, a reduced citrate synthase activity, a drop in membrane potential and an associated misbalanced mitochondrial function were observed exclusively in MET inhibitor-sensitive cells. These data imply that interference with metabolic state can be considered an early indicator of efficient MET inhibition and particular changes reported here could be explored in the future as markers of efficacy of anti-MET therapies. This article is protected by copyright. All rights reserved.

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