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Entrectinib reverses cytostatic resistance through the inhibition of ABCB1 efflux transporter, but not the CYP3A4 drug-metabolizing enzyme.

Abstract：

:Entrectinib is a new tyrosine kinase inhibitor that was recently approved for the treatment of ROS1-positive metastatic non-small cell lung cancer (NSCLC). In this study, we aimed to characterize its potential to act as a modulator of pharmacokinetic cytostatic resistance and perpetrator of drug interactions. In accumulation studies, entrectinib exhibited potent inhibition of ABCB1, while only moderate interaction was recorded for ABCG2 and ABCC1 efflux transporters. Furthermore, incubation assays revealed the potential of this drug to inhibit various recombinant cytochrome P450 enzymes, which can be ranked according to inhibitory affinities as follows: CYP2C8 ≈ CYP3A4 > CYP2C9 > CYP2C19 ≈ CYP3A5 > CYP2D6 > CYP2B6 > CYP1A2. Additionally, in silico docking analysis confirmed entrectinib's interactions with ABCB1 and CYP3A4 and resolved their possible molecular background. In subsequent drug combination experiments, we demonstrated the ability of entrectinib to synergize with daunorubicin in various ABCB1-expressing cellular models. Moreover, the comparative proliferation study results suggested that the anticancer efficacy of entrectinib is not affected by the functional presence of tested ABC transporters. In contrast to ABCB1-related data, no resistance reversal effect was recorded for the combination with docetaxel in HepG2-CYP3A4 cells. In the final experimental set, we observed no significant changes in ABCB1, ABCG2, ABCC1 or CYP3A4 gene expression in NSCLC cells exposed to entrectinib. In summary, our work indicates that entrectinib may be a perpetrator of clinically relevant pharmacokinetic drug interactions and modulator of ABCB1-mediated resistance. Our in vitro results might provide a valuable foundation for future clinical investigations.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Vagiannis D,Yu Z,Novotna E,Morell A,Hofman J

doi

10.1016/j.bcp.2020.114061

subject

Has Abstract

pub_date

2020-08-01 00:00:00

pages

114061

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(20)30295-1

journal_volume

178

pub_type

杂志文章

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Entrectinib reverses cytostatic resistance through the inhibition of ABCB1 efflux transporter, but not the CYP3A4 drug-metabolizing enzyme.