Elevated BCRP/ABCG2 expression confers acquired resistance to gefitinib in wild-type EGFR-expressing cells |
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Authors: | Chen Yun-Ju Huang Wei-Chien Wei Ya-Ling Hsu Sheng-Chieh Yuan Ping Lin Heather Y Wistuba Ignacio I Lee J Jack Yen Chia-Jui Su Wu-Chou Chang Kwang-Yu Chang Wen-Chang Chou Tse-Chuan Chou Chao-Kai Tsai Chang-Hai Hung Mien-Chie |
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Institution: | Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan. |
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Abstract: | BackgroundThe 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 FindingsHere, 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/SignificanceThus, 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. |
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