Impact of Q141K on the Transport of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors by ABCG2.

Yutaka Inoue,Yoichi Nakamura,Hiroshi Nakagawa,Takashi Morita,Tohru Kishino,Masami Kondo,Mari Onozuka,Yoji Ikegami,Kazumi Sano,Kazuhiko Hanada,Ken-Ichi Saito

doi:10.3390/cells8070763

Abstract

The ATP-binding cassette transporter ABCG2 is expressed in various organs, such as the small intestine, liver, and kidney, and influences the pharmacokinetics of drugs that are its substrates. ABCG2 is also expressed by cancer cells and mediates resistance to anticancer agents by promoting the efflux of these drugs. In the present study, we investigated the interactions between epidermal growth factor receptor tyrosine kinase inhibitors and ABCG2 by MTT assay, intracellular drug accumulation assay, and FACS. This study showed that four epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) (gefitinib, erlotinib, lapatinib, and afatinib) were transported from tumor cells as substrates of ABCG2. Q141K is a common single-nucleotide polymorphism of ABCG2 in Asians. We demonstrated that the extracellular efflux of gefitinib, erlotinib, and lapatinib was reduced by Q141K, whereas afatinib transport was not affected. In addition, all four EGFR TKIs inhibited the transport of other substrates by both wild-type and variant ABCG2 at 0.1 μM concentrations. Accordingly, epidermal growth factor receptor tyrosine kinase inhibitors may induce interactions with other drugs that are substrates of ABCG2, and single-nucleotide polymorphisms of ABCG2 may influence both the pharmacokinetics and efficacy of these anticancer agents.

Highlights

ABCG2 is a membrane-associated glycoprotein that is a member of the ATP-binding cassette (ABC) transporter superfamily
We found that the Q141K variant was associated with reduced transport of gefitinib, erlotinib, and lapatinib compared with wild-type ABCG2, while it had no influence on afatinib transport
ABCG2 is a key transporter related to resistance to anticancer agents and is expressed by various cancers, including lung cancer and colorectal cancer [13,23]

Summary

Introduction

ABCG2 is a membrane-associated glycoprotein that is a member of the ATP-binding cassette (ABC) transporter superfamily. ABCG2 is a half transporter and forms homodimers to actively excrete substrates from cells. There have been many reports of interactions between ABCG2 and tyrosine kinase inhibitors [1,8,9]. Gefitinib and erlotinib are epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) that are substrates of ABCG2 [10,11]. Expression of ABCG2 has been reported in both lung cancer and breast cancer, suggesting that it may influence tumor resistance and the pharmacokinetics of EGFR TKIs [12,13,14]. EGFR TKIs have been reported to inhibit the transport of other substrates by ABCG2, suggesting that drug interactions may occur in patients taking these anticancer agents. We found that gefitinib inhibits both ABCB1 and ABCG2, and that the antitumor activity, tumor tissue, and blood concentrations of SN-38 (the active metabolite of irinotecan) are increased in tumor-bearing mice by administration of gefitinib in combination with irinotecan [9]

Methods

Results

Conclusion