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

被引：61

作者：

Chen, Yun-Ju ^{[1
]}

Huang, Wei-Chien ^{[1
,3
,4
,12
]}

Wei, Ya-Ling ^{[1
]}

Hsu, Sheng-Chieh ^{[1
]}

Yuan, Ping ^{[7
]}

Lin, Heather Y. ^{[8
]}

Wistuba, Ignacio I. ^{[7
]}

Lee, J. Jack ^{[8
]}

Yen, Chia-Jui ^{[10
]}

Su, Wu-Chou ^{[10
]}

Chang, Kwang-Yu ^{[14
]}

Chang, Wen-Chang ^{[9
]}

Chou, Tse-Chuan ^{[11
,15
]}

Chou, Chao-Kai ^{[6
]}

Tsai, Chang-Hai ^{[2
,5
,13
]}

Hung, Mien-Chie ^{[1
,6
]}

机构：

[1] China Med Univ Hosp, Ctr Mol Med, Taichung, Taiwan

[2] China Med Univ Hosp, Dept Pediat, Taichung, Taiwan

[3] China Med Univ, Grad Inst Canc Biol, Taichung, Taiwan

[4] China Med Univ, PhD Program Canc Biol & Drug Discovery, Taichung, Taiwan

[5] China Med Univ, Grad Inst Basic Med Sci, Taichung, Taiwan

[6] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA

[9] Natl Cheng Kung Univ, Dept Pharmacol, Tainan 70101, Taiwan

[10] Natl Cheng Kung Univ, Inst Clin Med, Tainan 70101, Taiwan

[11] Natl Cheng Kung Univ, Dept Chem Engn, Tainan, Taiwan

[12] Asia Univ, Dept Biotechnol, Taichung, Taiwan

[13] Asia Univ, Dept Healthcare Adm, Taichung, Taiwan

[14] Natl Hlth Res Inst, Natl Inst Canc Res, Tainan, Taiwan

[15] Tatung Univ, Dept Chem Engn, Taipei 104, Taiwan

来源：

PLOS ONE | 2011年 / 6卷 / 06期

基金：

美国国家卫生研究院;

关键词：

TYROSINE KINASE INHIBITOR; FACTOR RECEPTOR MUTATIONS; LUNG-CANCER PATIENTS; MULTIDRUG-RESISTANCE; DRUG-RESISTANCE; ANTITUMOR-ACTIVITY; GENE-MUTATIONS; PHASE-II; ERLOTINIB; PROTEIN;

D O I：

10.1371/journal.pone.0021428

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：10

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