Tepotinib is a novel tyrosine kinase inhibitor recently approved for the treatment of non-small cell lung cancer (NSCLC). In this study, we evaluated the tepotinib's potential to perpetrate pharmacokinetic drug interactions and modulate multidrug resistance (MDR). Accumulation studies showed that tepotinib potently inhibits ABCB1 and ABCG2 efflux transporters, which was confirmed by molecular docking. In addition, tepotinib inhibited several recombinant cytochrome P450 (CYP) isoforms with varying potency. In subsequent drug combination experiments, tepotinib synergistically reversed daunorubicin and mitoxantrone resistance in cells with ABCB1 and ABCG2 overexpression, respectively. Remarkably, MDR-modulatory properties were confirmed in ex vivo explants derived from NSCLC patients. Furthermore, we demonstrated that anticancer effect of tepotinib is not influenced by the presence of ABC transporters associated with MDR, although monolayer transport assays designated it as ABCB1 substrate. Finally, tested drug was observed to have negligible effect on the expression of clinically relevant drug efflux transporters and CYP enzymes. In conclusion, our findings provide complex overview on the tepotinib's drug interaction profile and suggest a promising novel therapeutic strategy for future clinical investigations.

Department of Biochemical Sciences Faculty of Pharmacy in Hradec Králové Charles University Heyrovského 1203 500 05 Hradec Králové Czech Republic

Department of Cardiac Surgery Faculty of Medicine Charles University and University Hospital Hradec Králové Sokolská 581 500 05 Hradec Králové Czech Republic

Department of Chemistry Faculty of Science University of Hradec Králové Hradecká 1285 500 03 Hradec Králové Czech Republic

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Králové Charles University Heyrovského 1203 500 05 Hradec Králové Czech Republic

Institute of Biotechnology Brandenburg University of Technology Cottbus Senftenberg Universitätsplatz 1 01968 Senftenberg Germany

The Fingerland Department of Pathology Faculty of Medicine Charles University and University Hospital Hradec Králové Sokolská 581 500 05 Hradec Králové Czech Republic

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