Multidrug transporter ABCG2 prevents tumor cell death induced by the epidermal growth factor receptor inhibitor Iressa (ZD1839, Gefitinib)

被引:196
作者
Elkind, NB
Szentpétery, Z
Apáti, A
Özvegy-Laczka, C
Várady, G
Ujhelly, O
Szabó, K
Homolya, L
Váradi, A
Buday, L
Kéri, G
Német, K
Sarkadi, B
机构
[1] Hungarian Acad Sci, Membrane Res Grp, Natl Med Ctr, Inst Haematol & Immunol, H-1113 Budapest, Hungary
[2] Hungarian Acad Sci, Biol Res Ctr, Inst Enzymol, Budapest, Hungary
[3] Semmelweis Univ, Hungarian Acad Sci, Dept Med Chem, Peptide Biochem Res Grp, Budapest, Hungary
[4] Semmelweis Univ, Hungarian Acad Sci, Dept Pathobiochem, Peptide Biochem Res Grp, Budapest, Hungary
[5] Semmelweis Univ, Hungarian Acad Sci, Dept Mol Biol, Peptide Biochem Res Grp, Budapest, Hungary
关键词
D O I
10.1158/0008-5472.CAN-04-3303
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 signaling-dependent 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.
引用
收藏
页码:1770 / 1777
页数:8
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