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Elevated BCRP/ABCG2 Expression Confers Acquired Resistance to Gefitinib in Wild-Type EGFR-Expressing Cells
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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121773/ https://www.ncbi.nlm.nih.gov/pubmed/21731744 http://dx.doi.org/10.1371/journal.pone.0021428 |
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author | 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 |
author_facet | 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 |
author_sort | Chen, Yun-Ju |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3121773 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-31217732011-06-30 Elevated BCRP/ABCG2 Expression Confers Acquired Resistance to Gefitinib in Wild-Type EGFR-Expressing Cells 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 PLoS One Research Article 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. Public Library of Science 2011-06-23 /pmc/articles/PMC3121773/ /pubmed/21731744 http://dx.doi.org/10.1371/journal.pone.0021428 Text en Chen et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article 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 Elevated BCRP/ABCG2 Expression Confers Acquired Resistance to Gefitinib in Wild-Type EGFR-Expressing Cells |
title | Elevated BCRP/ABCG2 Expression Confers Acquired Resistance to Gefitinib in Wild-Type EGFR-Expressing Cells |
title_full | Elevated BCRP/ABCG2 Expression Confers Acquired Resistance to Gefitinib in Wild-Type EGFR-Expressing Cells |
title_fullStr | Elevated BCRP/ABCG2 Expression Confers Acquired Resistance to Gefitinib in Wild-Type EGFR-Expressing Cells |
title_full_unstemmed | Elevated BCRP/ABCG2 Expression Confers Acquired Resistance to Gefitinib in Wild-Type EGFR-Expressing Cells |
title_short | Elevated BCRP/ABCG2 Expression Confers Acquired Resistance to Gefitinib in Wild-Type EGFR-Expressing Cells |
title_sort | elevated bcrp/abcg2 expression confers acquired resistance to gefitinib in wild-type egfr-expressing cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121773/ https://www.ncbi.nlm.nih.gov/pubmed/21731744 http://dx.doi.org/10.1371/journal.pone.0021428 |
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