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

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.

Medically Important Alterations in Transport Function and Trafficking of ABCG2

“…Numerous in vitro studies have demonstrated altered efflux of chemotherapeutic agents and reduced drug resistance in cancer cells expressing ABCG2 carrying various SNPs. While an unambiguous role for Q141K has been established, the results on the effect of the V12M variant were conflicting [ 100 , 115 , 133 , 172 ]. It is important to note that the specific activity of both V12M and Q141K, i.e., transport activity normalized by the expression level, remained unaltered [ 100 ], confirming that these SNPs do not affect the actual transport function.…”

“…It is important to note that the specific activity of both V12M and Q141K, i.e., transport activity normalized by the expression level, remained unaltered [ 100 ], confirming that these SNPs do not affect the actual transport function. ABCG2-Q141K has been shown to diminish drug efflux and/or to increase sensitivity to various anti-cancer drugs, including methotrexate, numerous TKIs (gefitinib, erlotinib, lapatinib, imatinib, dasatinib, nilotinib), and the topoisomerase I inhibitor indolocarbazole [ 100 , 114 , 115 , 133 , 172 , 173 ]. In addition to genetic alterations, epigenetic modifications could also modulate drug responses.…”

Racial Disparity in Drug Disposition in the Digestive Tract

“…Additionally, in vitro studies using different cell lines indicated that the ABCG2 C421A mutation decreased transport function. This was evidenced by lower intracellular accumulation or lower efflux of different BCRP substrates including estrone-3-sulfate, dehydroepiandrosterone-sulfate, p -aminohippuric acid, methotrexate, indolocarbazole, gefitinib, erlotinib, and lapatinib when compared to those in wild type cells [ 35 , 36 , 37 ]. In vitro activity studies also support the above-mentioned function loss.…”

“…In addition, since some SNPs express their protein products at a lower level compared to the wild type, it may be necessary to normalize intracellular drug accumulation or drug metabolism rate with the protein level to accurately evaluate protein function. For example, ABCG2 C421A transfected cells exhibited higher intracellular drug accumulation when compared to wild type cells in the above-mentioned studies [ 35 , 36 , 37 ]. Higher intracellular accumulation usually suggests loss of efflux function.…”

The ABCG2/BCRP transporter and its variants – from structure to pathology

“…The frequently occurring polymorphic and mutant forms of ABCG2 may directly modulate the effects of the therapeutic agents in the cancer cells [66,71,121]. The Q141K variant was found to be associated with reduced transport of gefitinib, erlotinib, and lapatinib, suggesting that Q141K, in addition to its effect on pharmacokinetics, may also directly modulate the cellular effects of these drugs [179,180]. Also, the presence of the ABCG2 minor variants may be related to increased drug toxicity [22,28,92,181].…”