期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 21, 页码 -出版社
MDPI
DOI: 10.3390/ijms222111936
关键词
tepotinib; non-small cell lung cancer; multidrug resistance; drug interaction; ABC transporter; cytochrome P450
资金
- Czech Science Foundation [20-20414Y]
- Grant Agency of Charles University [334120/C, 102121/C]
- Charles University [SVV/2021/260 549]
- University of Hradec Kralove [Faculty of Science] [VT2019-2021]
- European Funds for Regional Development (EFRE, Brandenburg, Germany) [85009748]
This study evaluated the potential of tepotinib to modulate multidrug resistance and drug interactions, showing promising results in reversing drug resistance in cells with overexpressed ABC transporters. Tepotinib also demonstrated potent inhibition of ABCB1 and ABCG2 efflux transporters and various recombinant cytochrome P450 isoforms. These findings suggest a novel therapeutic strategy for future clinical investigations.
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.
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