Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo

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 te...

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Autores principales:	Dimitrios Vagiannis, Youssif Budagaga, Anselm Morell, Yu Zhang, Eva Novotná, Adam Skarka, Sarah Kammerer, Jan-Heiner Küpper, Ivo Hanke, Tomáš Rozkoš, Jakub Hofman
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	tepotinib non-small cell lung cancer multidrug resistance drug interaction ABC transporter cytochrome P450 Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/0212eb51dc624676ad5bb0e9e6facdd1
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spelling	oai:doaj.org-article:0212eb51dc624676ad5bb0e9e6facdd12021-11-11T17:21:04ZTepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo10.3390/ijms2221119361422-00671661-6596https://doaj.org/article/0212eb51dc624676ad5bb0e9e6facdd12021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11936https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Tepotinib 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.Dimitrios VagiannisYoussif BudagagaAnselm MorellYu ZhangEva NovotnáAdam SkarkaSarah KammererJan-Heiner KüpperIvo HankeTomáš RozkošJakub HofmanMDPI AGarticletepotinibnon-small cell lung cancermultidrug resistancedrug interactionABC transportercytochrome P450Biology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11936, p 11936 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	tepotinib non-small cell lung cancer multidrug resistance drug interaction ABC transporter cytochrome P450 Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	tepotinib non-small cell lung cancer multidrug resistance drug interaction ABC transporter cytochrome P450 Biology (General) QH301-705.5 Chemistry QD1-999 Dimitrios Vagiannis Youssif Budagaga Anselm Morell Yu Zhang Eva Novotná Adam Skarka Sarah Kammerer Jan-Heiner Küpper Ivo Hanke Tomáš Rozkoš Jakub Hofman Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo
description	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.
format	article
author	Dimitrios Vagiannis Youssif Budagaga Anselm Morell Yu Zhang Eva Novotná Adam Skarka Sarah Kammerer Jan-Heiner Küpper Ivo Hanke Tomáš Rozkoš Jakub Hofman
author_facet	Dimitrios Vagiannis Youssif Budagaga Anselm Morell Yu Zhang Eva Novotná Adam Skarka Sarah Kammerer Jan-Heiner Küpper Ivo Hanke Tomáš Rozkoš Jakub Hofman
author_sort	Dimitrios Vagiannis
title	Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo
title_short	Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo
title_full	Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo
title_fullStr	Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo
title_full_unstemmed	Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo
title_sort	tepotinib inhibits several drug efflux transporters and biotransformation enzymes: the role in drug-drug interactions and targeting cytostatic resistance in vitro and ex vivo
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0212eb51dc624676ad5bb0e9e6facdd1
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Tepotinib Inhibits Several Drug Efflux Transporters and Biotransformation Enzymes: The Role in Drug-Drug Interactions and Targeting Cytostatic Resistance In Vitro and Ex Vivo

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