Elevated BCRP/ABCG2 Expression Confers Acquired Resistance to Gefitinib in Wild-Type EGFR-Expressing Cells

Yun Ju Chen, Wei Chien Huang, Ya Ling Wei, Sheng Chieh Hsu, Ping Yuan, Heather Y. Lin, Ignacio I. Wistuba, J. Jack Lee, Chia Jui Yen, Wu Chou Su, Kwang Yu Chang, Wen Chang Chang, Tse Chuan Chou, Chao Kai Chou, Chang Hai Tsai, Mien Chie Hung

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71 Citations (Scopus)


Background: The sensitivity of non-small cell lung cancer (NSCLC) patients to EGFR tyrosine kinase inhibitors (TKIs) is strongly associated with activating EGFR mutations. Although not as sensitive as patients harboring these mutations, some patients with wild-type EGFR (wtEGFR) remain responsive to EGFR TKIs, suggesting that the existence of unexplored mechanisms renders most of wtEGFR-expressing cancer cells insensitive. Methodology/Principal Findings: Here, we show that acquired resistance of wtEGFR-expressing cancer cells to an EGFR TKI, gefitinib, is associated with elevated expression of breast cancer resistance protein (BCRP/ABCG2), which in turn leads to gefitinib efflux from cells. In addition, BCRP/ABCG2 expression correlates with poor response to gefitinib in both cancer cell lines and lung cancer patients with wtEGFR. Co-treatment with BCRP/ABCG2 inhibitors enhanced the anti-tumor activity of gefitinib. Conclusions/Significance: Thus, BCRP/ABCG2 expression may be a predictor for poor efficacy of gefitinib treatment, and targeting BCRP/ABCG2 may broaden the use of gefitinib in patients with wtEGFR.

Original languageEnglish
Article numbere21428
JournalPLoS ONE
Issue number6
Publication statusPublished - 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General


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