Metabolomics reveals tepotinib‐related mitochondrial dysfunction in MET‐activating mutations‐driven models
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Date
2019-07
Publication Type
Journal Article
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yes
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Abstract
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.
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published
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Journal / series
Volume
286 (14)
Pages / Article No.
2692 - 2710
Publisher
Wiley
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Subject
MET receptor tyrosine kinase; Metabolism; Mitochondria; Non-targeted mass spectrometry; Small molecule inhibitor
Organisational unit
08839 - Zamboni, Nicola (Tit.-Prof.)