z-logo
Premium
Metabolomics reveals tepotinib‐related mitochondrial dysfunction in MET ‐activating mutations‐driven models
Author(s) -
Poliaková Michaela,
Felser Andrea,
Pierzchala Katarzyna,
Nuoffer JeanMarc,
Aebersold Daniel Matthias,
Zimmer Yitzhak,
Zamboni Nicola,
Medová Michaela
Publication year - 2019
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14852
Subject(s) - serine , metabolomics , citric acid cycle , biochemistry , gluconeogenesis , biology , metabolism , chemistry , phosphorylation , bioinformatics
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 toward 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 content is not available in your region!

Continue researching here.

Having issues? You can contact us here