Multidrug Transporter ABCG2 Prevents Tumor Cell Death Induced by the Epidermal Growth Factor Receptor Inhibitor Iressa (ZD1839, Gefitinib)

Abstract

Iressa (ZD1839, Gefitinib), used in clinics to treat non-small cell lung cancer patients, is a tyrosine kinase receptor inhibitor that leads to specific decoupling of epidermal growth factor receptor (EGFR) signaling. Recent data indicate that Iressa is especially effective in tumors with certain EGFR mutations; however, a subset of these tumors does not respond to Iressa. In addition, certain populations have an elevated risk of side effects during Iressa treatment. The human ABCG2 (BCRP/MXR/ABCP) transporter causes cancer drug resistance by actively extruding a variety of cytotoxic drugs, and it functions physiologically to protect our tissues from xenobiotics. Importantly, ABCG2 modifies absorption, distribution, and toxicity of several pharmacologic agents. Previously, we showed that ABCG2 displays a high-affinity interaction with several tyrosine kinase receptor inhibitors, including Iressa. Here, we show that the expression of ABCG2, but not its nonfunctional mutant, protects the EGFR signalingdependent A431 tumor cells from death on exposure to Iressa. This protection is reversed by the ABCG2-specific inhibitor, Ko143. These data, reinforced with cell biology and biochemical experiments, strongly suggest that ABCG2 can actively pump Iressa. Therefore, variable expression and polymorphisms of ABCG2 may significantly modify the antitumor effect as well as the absorption and tissue distribution of Iressa. (Cancer Res 2005; 65(5): 1770-7)

Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors

“…These results suggest that, as discussed above for imatinib, gefitinib might also have a narrow window, especially in a low concentration range, where its active transport by BCRP is efficient. Consistent with gefitinib being a BCRP substrate, BCRP-transduced A431 cells were resistant to gefitinib compared with the parental cell line (Yanase et al, 2004;Elkind et al, 2005) and the resistant phenotype was reversed by the BCRP-specific inhibitor Ko143 (Elkind et al, 2005). Of note, consistent with EGFR amplification and dependence on EGFR signalling for survival, A431 cells are highly sensitive to gefitinib, with IC 50 values in the nanomolar range.…”

“…Most likely, the apparent discrepancy in these results is due to the selected concentrations of gefitinib used in the different studies. Elkind et al (2005) showed that low concentrations of gefitinib (o1 mM) significantly activated BCRP-ATPase activity in isolated membranes of BCRP-expressing mammalian MCF-7/MX and A431 cells, whereas higher concentrations (41 mM) had a markedly lower stimulatory effect. Consequently, this might explain the lack of gefitinib transport into vesicles of PC-6/SN2-5H cells, since a gefitinib concentration of 30 mM was used in this study (Nakamura et al, 2005).…”

“…Contradictory data have been published also for the epidermal growth factor receptor (EGFR) TKI gefitinib, since some authors describe it as a BCRP substrate, while others classified it as an inhibitor and not a substrate (Elkind et al, 2005;Nakamura et al, 2005). Most likely, the apparent discrepancy in these results is due to the selected concentrations of gefitinib used in the different studies.…”

“…Thus, it has been hypothesised that BCRP is one of the determinants of gefitinib resistance in cells that express EGFR and show EGFR-dependent growth (Yanase et al, 2004). In fact, Elkind et al (2005) have shown that BCRP expression protects cells from gefitinib-mediated inhibition of EGFR phosphorylation and subsequent apoptosis. This suggests that BCRP prevents the action of gefitinib by effluxing this compound from the cell before it can interact with plasma membrane-associated EGFR.…”

Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors

“…Shorter CA repeat lengths were associated with poorer survival in the absence of therapy with an EGFR TKI, which is a reversal of expectations in TKI-treated patients (Dubey et al, 2006). The multidrug transporter ABCG2 was shown to be active in removing gefitinib from cells (Elkind et al, 2005). In published reports, ABCG2 polymorphisms have been identified as being associated with increased EGFR TKI concentrations, toxicity or both, in patients treated with gefitinib and erlotinib (Cusatis et al, 2006;Li et al, 2007;Rudin et al, 2008).…”