Encorafenib (LGX818, trade name Braftovi), a novel BRAF inhibitor, has been approved for the treatment of melanoma and colorectal cancer. In the present work, we evaluated encorafenib's possible antagonistic effects on the pharmacokinetic mechanisms of multidrug resistance (MDR), as well as its perpetrator role in drug interactions. Firstly, encorafenib potently inhibited the efflux function of the ABCC1 transporter in drug accumulation assays, while moderate and null interaction levels were recorded for ABCB1 and ABCG2, respectively. In contrast, the mRNA expression levels of all the tested transporters were not altered by encorafenib. In the drug combination studies, we found that daunorubicin and topotecan resistances were synergistically attenuated by the encorafenib-mediated interaction in A431-ABCC1 cells. Notably, further experiments in ex vivo patient-derived explants confirmed the MDR-modulating ability of encorafenib. Advantageously, the overexpression of tested drug efflux transporters failed to hinder the antiproliferative activity of encorafenib. In addition, no significant modulation of the CYP3A4 enzyme's activity by encorafenib was observed. In conclusion, our work indicated that encorafenib can act as an effective chemosensitizer targeting the ABCC1-induced MDR. Our in vitro and ex vivo data might provide valuable information for designing the novel effective scheme applicable in the clinical pharmacotherapy of BRAF-mutated/ABCC1-expressing tumors.

• Klíčová slova
• ABC transporter, cytochrome P450, encorafenib, multidrug resistance, non-small cell lung cancer,
• Publikační typ
• časopisecké články MeSH

Talazoparib (Talzenna) is a novel poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that is clinically used for the therapy of breast cancer. Furthermore, the drug has shown antitumor activity against different cancer types, including non-small cell lung cancer (NSCLC). In this work, we investigated the possible inhibitory interactions of talazoparib toward selected ATP-binding cassette (ABC) drug efflux transporters and cytochrome P450 biotransformation enzymes (CYPs) and evaluated its position in multidrug resistance (MDR). In accumulation studies, talazoparib interacted with the ABCC1 and ABCG2 transporters, but there were no significant effects on ABCB1. Furthermore, incubation assays revealed a negligible capacity of the tested drug to inhibit clinically relevant CYPs. In in vitro drug combination experiments, talazoparib synergistically reversed daunorubicin and mitoxantrone resistance in cells with ABCC1 and ABCG2 expression, respectively. Importantly, the position of an effective MDR modulator was further confirmed in drug combinations performed in ex vivo NSCLC patients-derived explants, whereas the possible victim role was refuted in comparative proliferation experiments. In addition, talazoparib had no significant effects on the mRNA-level expressions of MDR-related ABC transporters in the MCF-7 cellular model. In summary, our study presents a comprehensive overview on the pharmacokinetic drug-drug interactions (DDI) profile of talazoparib. Moreover, we introduced talazoparib as an efficient MDR antagonist.

• Klíčová slova
• ABC transporter, cytochrome P450, multidrug resistance, pharmacokinetic drug–drug interaction, small cell lung cancer, talazoparib,
• MeSH
• ABC transportér z rodiny G, člen 2 genetika   MeSH
• ABC transportéry genetika   metabolismus   MeSH
• lidé MeSH
• mnohočetná léková rezistence MeSH
• nádorové proteiny metabolismus   MeSH
• nádory plic * MeSH
• nemalobuněčný karcinom plic * farmakoterapie   genetika   MeSH
• P-glykoproteiny genetika   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 MeSH
• ABC transportéry MeSH
• ABCB1 protein, human MeSH Prohlížeč
• ABCG2 protein, human MeSH Prohlížeč
• nádorové proteiny MeSH
• P-glykoproteiny MeSH
• systém (enzymů) cytochromů P-450 MeSH
• talazoparib MeSH Prohlížeč

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.

• Klíčová slova
• ABC transporter, cytochrome P450, drug interaction, multidrug resistance, non-small cell lung cancer, tepotinib,
• MeSH
• ABC transportéry antagonisté a inhibitory   MeSH
• chemorezistence účinky léků   MeSH
• cytostatické látky farmakologie   MeSH
• lékové interakce * MeSH
• lidé MeSH
• mnohočetná léková rezistence účinky léků   MeSH
• nádory plic farmakoterapie   metabolismus   patologie   MeSH
• nemalobuněčný karcinom plic farmakoterapie   metabolismus   patologie   MeSH
• piperidiny farmakologie   MeSH
• protinádorové látky farmakologie   MeSH
• pyridaziny farmakologie   MeSH
• pyrimidiny farmakologie   MeSH
• techniky in vitro MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportéry MeSH
• cytostatické látky MeSH
• piperidiny MeSH
• protinádorové látky MeSH
• pyridaziny MeSH
• pyrimidiny MeSH
• tepotinib MeSH Prohlížeč