Metabolomics reveals tepotinib-related mitochondrial dysfunction in MET-activating mutations-driven models

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Genetic aberrations in the MET receptor tyrosine kinase drive oncogenic addiction in various human cancers.
• MET is a viable target for anticancer therapies.
• MET signaling influences cellular metabolic phenotypes.

Purpose of the Study:

• To investigate the role of MET signaling in cancer cell metabolism.
• To characterize the metabolic alterations induced by MET inhibition.
• To identify potential early biomarkers for MET-targeted therapy efficacy.

Main Methods:

• Utilized cellular models with MET-activating mutations (sensitive and resistant to inhibitors).
• Administered the MET inhibitor tepotinib and assessed cell viability, apoptosis, and metabolic profiles via metabolite ion analysis.
• Performed functional assays including oxygen consumption rate, citrate synthase activity, and mitochondrial membrane potential measurements.

Main Results:

• Tepotinib treatment decreased viability and increased apoptosis in sensitive cells.
• MET inhibition led to significant reductions in amino sugar, gluconeogenesis, glycine/serine, and TCA cycle metabolites.
• Sensitive cells exhibited decreased oxygen consumption, reduced citrate synthase activity, and impaired mitochondrial function.

Conclusions:

• MET signaling significantly impacts cancer cell metabolism.
• Altered metabolic signatures and mitochondrial dysfunction are early indicators of effective MET inhibition.
• Metabolic changes observed could serve as predictive biomarkers for anti-MET therapies.