Beschreibung:
<jats:p>Genetic aberrations in the hepatocyte growth factor receptor tyrosine kinase <jats:styled-content style="fixed-case">MET</jats:styled-content> induce oncogenic addiction in various types of human cancers, advocating <jats:styled-content style="fixed-case">MET</jats:styled-content> as a viable anticancer target. Here, we report that <jats:styled-content style="fixed-case">MET</jats:styled-content> signaling plays an important role in conferring a unique metabolic phenotype to cellular models expressing <jats:styled-content style="fixed-case">MET</jats:styled-content>‐activating mutated variants that are either sensitive or resistant toward <jats:styled-content style="fixed-case">MET</jats:styled-content> small molecule inhibitors. <jats:styled-content style="fixed-case">MET</jats:styled-content> phosphorylation downregulated by the specific <jats:styled-content style="fixed-case">MET</jats:styled-content> inhibitor tepotinib resulted in markedly decreased viability and increased apoptosis in tepotinib‐sensitive cells. Moreover, prior to the induction of <jats:styled-content style="fixed-case">MET</jats:styled-content> 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 <jats:styled-content style="fixed-case">TCA</jats:styled-content> 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 <jats:styled-content style="fixed-case">MET</jats:styled-content> inhibitor‐sensitive cells. These data imply that interference with metabolic state can be considered an early indicator of efficient <jats:styled-content style="fixed-case">MET</jats:styled-content> inhibition and particular changes reported here could be explored in the future as markers of efficacy of anti‐<jats:styled-content style="fixed-case">MET</jats:styled-content> therapies.</jats:p>