000265399 001__ 265399
000265399 005__ 20190722134223.0
000265399 0247_ $$2doi$$a10.1111/febs.14852
000265399 02470 $$2PMID$$a30993872
000265399 037__ $$aARTICLE
000265399 245__ $$aMetabolomics reveals tepotinib‐related mitochondrial dysfunction in MET activating mutations‐driven models
000265399 260__ $$c2019-04-16
000265399 269__ $$a2019-04-16
000265399 336__ $$aJournal Articles
000265399 500__ $$aAhead of print - April 2019
000265399 520__ $$aGenetic aberrations in the hepatocyte growth factor receptor tyrosine kinase MET induce oncogenic addiction in various types of human cancers, advocating MET as a viable anticancer target. Here, we report that MET signaling plays an important role in conferring a unique metabolic phenotype to cellular models expressing MET-activating mutated variants that are either sensitive or resistant towards MET small molecule inhibitors. MET phosphorylation downregulated by the specific MET inhibitor tepotinib resulted in markedly decreased viability and increased apoptosis in tepotinib-sensitive cells. Moreover, prior to the induction of MET inhibition-dependent cell death, tepotinib also led to an altered metabolic signature, characterized by a prominent reduction of metabolite ions related to amino sugar metabolism, gluconeogenesis, glycine and serine metabolism and of numerous TCA cycle-related metabolites such as succinate, malate and citrate. Functionally, a decrease in oxygen consumption rate, a reduced citrate synthase activity, a drop in membrane potential and an associated misbalanced mitochondrial function were observed exclusively in MET inhibitor-sensitive cells. These data imply that interference with metabolic state can be considered an early indicator of efficient MET inhibition and particular changes reported here could be explored in the future as markers of efficacy of anti-MET therapies.
000265399 6531_ $$aCIBM-AIT
000265399 700__ $$aPoliaková, Michaela
000265399 700__ $$aFelser, Andrea
000265399 700__ $$g174355$$aPierzchala, Katarzyna
000265399 700__ $$aNuoffer, Jean‐Marc
000265399 700__ $$aAebersold, Daniel Matthias
000265399 700__ $$aZimmer, Yitzhak
000265399 700__ $$aZamboni, Nicola
000265399 700__ $$aMedová, Michaela
000265399 773__ $$tThe FEBS Journal$$j286$$k14$$q2692-2710
000265399 8560_ $$frolf.gruetter@epfl.ch
000265399 909C0 $$zPasquier, Simon$$xU10984$$pLIFMET$$mrolf.gruetter@epfl.ch$$0252276
000265399 909C0 $$zPasquier, Simon$$xU12623$$pCIBM$$mrolf.gruetter@epfl.ch$$0252477
000265399 909CO $$pSB$$particle$$ooai:infoscience.epfl.ch:265399
000265399 960__ $$arolf.gruetter@epfl.ch
000265399 961__ $$aalessandra.bianchi@epfl.ch
000265399 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000265399 980__ $$aARTICLE
000265399 981__ $$aoverwrite