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1. Biochem Pharmacol. 2012 Apr 21. [Epub ahead of print]

Interaction of the EGFR inhibitors gefitinib, vandetanib, pelitinib and neratinib
with the ABCG2 multidrug transporter: Implications for the emergence and reversal
of cancer drug resistance.

Hegedüs C, Truta-Feles K, Antalffy G, Várady G, Német K, Ozvegy-Laczka C, Kéri G,
Orfi L, Szakács G, Settleman J, Váradi A, Sarkadi B.

Membrane Research Group of the Hungarian Academy of Sciences, Department of
Biophysics, Semmelweis University and National Blood Center, Budapest, Hungary.

Human ABCG2 is a plasma membrane glycoprotein that provides physiological
protection against xenobiotics. ABCG2 also significantly influences
biodistribution of drugs through pharmacological tissue barriers and confers
multidrug resistance to cancer cells. Moreover, ABCG2 is the molecular
determinant of the side population that is characteristically enriched in normal
and cancer stem cells. Numerous tumors depend on unregulated EGFR signaling, thus
inhibition of this receptor by small molecular weight inhibitors such as
gefitinib, and the novel second generation agents vandetanib, pelitinib and
neratinib, is a promising therapeutic option. In the present study, we provide
detailed biochemical characterization regarding the interaction of these EGFR
inhibitors with ABCG2. We show that ABCG2 confers resistance to gefitinib and
pelitinib, whereas the intracellular action of vandetanib and neratinib is
unaltered by the presence of the transporter. At higher concentrations, however,
all these EGFR inhibitors inhibit ABCG2 function, thereby promoting accumulation
of ABCG2 substrate drugs. We also report enhanced expression of ABCG2 in
gefitinib-resistant non-small cell lung cancer cells, suggesting potential
clinical relevance of ABCG2 in acquired drug resistance. Since ABCG2 has
important impact on both the pharmacological properties and anti-cancer
efficiencies of drugs, our results regarding the novel EGFR inhibitors should
provide useful information about their therapeutic applicability against
ABCG2-expressing cancer cells depending on EGFR signaling. In addition, the
finding that these EGFR inhibitors efficiently block ABCG2 function may help to
design novel drug-combination therapeutic strategies.

Copyright © 2012 Elsevier Inc. All rights reserved.

PMID: 22548830 [PubMed - as supplied by publisher]