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

[img] Text
Poliakov-_et_al-2019-The_FEBS_Journal.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (1MB) | Request a copy

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie

UniBE Contributor:

Poliaková, Michaela; Felser, Andrea Debora; Nuoffer, Jean-Marc; Aebersold, Daniel; Zimmer, Yitzhak and Medova, Michaela

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1742-464X

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Beatrice Scheidegger

Date Deposited:

15 Jul 2019 11:29

Last Modified:

22 Oct 2019 22:56

Publisher DOI:

10.1111/febs.14852

PubMed ID:

30993872

Uncontrolled Keywords:

MET receptor tyrosine kinase metabolism mitochondria non-targeted mass spectrometry small molecule inhibitor

BORIS DOI:

10.7892/boris.130381

URI:

https://boris.unibe.ch/id/eprint/130381

Actions (login required)

Edit item Edit item
Provide Feedback