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

Abstract

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.

Encorafenib Acts as a Dual-Activity Chemosensitizer through Its Inhibitory Effect on ABCC1 Transporter In Vitro and Ex Vivo

“…After the lung lobectomy, tumor tissue was immediately excised by the pathologist to collect an NSCLC sample. The isolation of lung cancer cells was based on the method reported in published papers with minor optimizations [18][19][20]. Fragmented pieces 2-5 mm in diameter were separated from the tumor samples using a scalpel.…”

“…Cell viability was evaluated based on the MTT assay as described in our previous papers [19,20]. The cells were seeded in 96-well plates at the following densities for a 24-h incubation: MDCKII-par, MDCKII-ABCB1, MDCKII-ABCG2, and MDCKII-ABCC1: 1.5 × 10 4 cells/well; A431-par, A431-ABCB1, A431-ABCG2, and A431-ABCC1: 2.0 × 10 4 cells/well; NCI-H2228: 1.2 × 10 4 cells/well; HCC827: 4.0 × 10 4 cells/well; NSCLC primary culture cells: 1.0 × 10 4 cells/well.…”

“…Drug combination studies in A431 and NSCLC primary culture cells were carried out similarly as in our previous descriptions [19,20,22]. Cells were seeded in 96-well plates at their specific densities as mentioned above.…”

“…Western blotting experiments were performed according to the previous description [19,20]. Briefly, proteins from the primary culture samples were isolated when the cells reached full confluency in Petri dishes.…”

Tepotinib for advanced non-small-cell lung cancer with MET exon 14 skipping mutations

“… 4 The pharmacokinetic interaction of tepotinib with ATP-binding cassette transporters and cytochrome P -450 (CYP) drug-metabolising enzymes as well as their possibility to combat multidrug resistance were explored in vivo and in vitro . 5 Metabolism and in vitro data showed that tepotinib is a substrate of CYP3A4, CYP2C8 and P-glycoprotein (P-gp). However, it is not possible to accurately quantify the fractions metabolised by the individual major CYP isoenzymes.…”