Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
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
_version_ 1782206869723414528
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
work_keys_str_mv AT chenyunju elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells
AT huangweichien elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells
AT weiyaling elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells
AT hsushengchieh elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells
AT yuanping elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells
AT linheathery elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells
AT wistubaignacioi elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells
AT leejjack elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells
AT yenchiajui elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells
AT suwuchou elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells
AT changkwangyu elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells
AT changwenchang elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells
AT choutsechuan elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells
AT chouchaokai elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells
AT tsaichanghai elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells
AT hungmienchie elevatedbcrpabcg2expressionconfersacquiredresistancetogefitinibinwildtypeegfrexpressingcells