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

Biochem Pharmacol. 2012 Aug 1;84(3):260-7. doi: 10.1016/j.bcp.2012.04.010. Epub 2012 Apr 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / metabolism*
  • ATP-Binding Cassette Transporters / physiology
  • Aminoquinolines / chemistry
  • Aminoquinolines / metabolism*
  • Aminoquinolines / pharmacology
  • Aniline Compounds / chemistry
  • Aniline Compounds / metabolism*
  • Aniline Compounds / pharmacology
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Cell Line
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Drug Resistance, Neoplasm / drug effects
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism*
  • Gefitinib
  • Humans
  • Neoplasm Proteins / metabolism*
  • Neoplasm Proteins / physiology
  • Piperidines / chemistry
  • Piperidines / metabolism*
  • Piperidines / pharmacology
  • Protein Binding / drug effects
  • Quinazolines / chemistry
  • Quinazolines / metabolism*
  • Quinazolines / pharmacology
  • Quinolines / chemistry
  • Quinolines / metabolism*
  • Quinolines / pharmacology


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Aminoquinolines
  • Aniline Compounds
  • Antineoplastic Agents
  • Neoplasm Proteins
  • Piperidines
  • Quinazolines
  • Quinolines
  • EGFR protein, human
  • ErbB Receptors
  • neratinib
  • Gefitinib
  • EKB 569
  • N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine