title: Elevated BCRP/ABCG2 expression confers acquired resistance to gefitinib in wild-type EGFR-expressing cells.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors: Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
authors: Yun-Ju
authors: YJ
authors: Chen
authors: Wei-Chien
authors: WC
authors: Huang
authors: Ya-Ling
authors: YL
authors: Wei
authors: Sheng-Chieh
authors: SC
authors: Hsu
authors: Ping
authors: P
authors: Yuan
authors: Heather Y
authors: HY
authors: Lin
authors: Ignacio I
authors: II
authors: Wistuba
authors: J Jack
authors: JJ
authors: Lee
authors: Chia-Jui
authors: CJ
authors: Yen
authors: Wu-Chou
authors: WC
authors: Su
authors: Kwang-Yu
authors: KY
authors: Chang
authors: Wen-Chang
authors: WC
authors: Chang
authors: Tse-Chuan
authors: TC
authors: Chou
authors: Chao-Kai
authors: CK
authors: Chou
authors: Chang-Hai
authors: CH
authors: Tsai
authors: Mien-Chie
authors: MC
authors: Hung
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000378:metabolism*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000378:metabolism / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D011799:Quinazolines; D034741:RNA, Small Interfering; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib