Collateral chemoresistance to anti- microtubule agents in a lung cancer cell line with acquired resistance to erlotinib

Hiroshi Mizuuchi, Kenichi Suda, Katsuaki Sato, Shuta Tomida, Yoshihiko Fujita, Yoshihisa Kobayashi, Yoshihiko Maehara, Yoshitaka Sekido, Kazuto Nishio, Tetsuya Mitsudomi

Research output: Contribution to journalArticle

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Abstract

Various alterations underlying acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been described. Although treatment strategies specific for these mechanisms are under development, cytotoxic agents are currently employed to treat many patients following failure of EGFR-TKIs. However, the effect of TKI resistance on sensitivity to these cytotoxic agents is mostly unclear. This study investigated the sensitivity of erlotinib-resistant tumor cells to five cytotoxic agents using an in vitro EGFR-TKI-resistant model. Four erlotinib-sensitive lung adenocarcinoma cell lines and their resistant derivatives were tested. Of the resistant cell lines, all but one showed a similar sensitivity to the tested drugs as their parental cells. HCC4006ER cells with epithelial mesenchymal transition features acquired resistance to the three microtubule-targeting agents, docetaxel, paclitaxel and vinorelbine, but not to cisplatin and gemcitabine. Gene expression array and immunoblotting demonstrated that ATP-binding cassette subfamily B, member 1 (ABCB1) was up-regulated in HCC4006ER cells. ABCB1 knockdown by siRNA partially restored sensitivity to the anti-microtubule agents but not to erlotinib. Moreover, the histone deacetylase inhibitor entinostat sensitized HCC4006ER cells to anti-microtubule agents through ABCB1 suppression. Our study indicates that sensitivity of tumor cells to cytotoxic agents in general does not change before and after failure of EGFR-TKIs. However, we describe that two different molecular alterations confer acquired resistance to EGFR-TKIs and cytotoxic agents, respectively. This phenomenon should be kept in mind in selection of subsequent therapy after failure of EGFR-TKIs.

Original languageEnglish
Article numbere0123901
JournalPloS one
Volume10
Issue number4
DOIs
Publication statusPublished - Feb 23 2015

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lung neoplasms
Epidermal Growth Factor Receptor
Microtubules
Protein-Tyrosine Kinases
Cytotoxins
microtubules
tyrosine
Lung Neoplasms
phosphotransferases (kinases)
Cells
cell lines
Cell Line
Adenosine Triphosphate
docetaxel
gemcitabine
Tumors
cells
histone deacetylase
cisplatin
Histone Deacetylase Inhibitors

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Mizuuchi, H., Suda, K., Sato, K., Tomida, S., Fujita, Y., Kobayashi, Y., ... Mitsudomi, T. (2015). Collateral chemoresistance to anti- microtubule agents in a lung cancer cell line with acquired resistance to erlotinib. PloS one, 10(4), [e0123901]. https://doi.org/10.1371/journal.pone.0123901

Collateral chemoresistance to anti- microtubule agents in a lung cancer cell line with acquired resistance to erlotinib. / Mizuuchi, Hiroshi; Suda, Kenichi; Sato, Katsuaki; Tomida, Shuta; Fujita, Yoshihiko; Kobayashi, Yoshihisa; Maehara, Yoshihiko; Sekido, Yoshitaka; Nishio, Kazuto; Mitsudomi, Tetsuya.

In: PloS one, Vol. 10, No. 4, e0123901, 23.02.2015.

Research output: Contribution to journalArticle

Mizuuchi, H, Suda, K, Sato, K, Tomida, S, Fujita, Y, Kobayashi, Y, Maehara, Y, Sekido, Y, Nishio, K & Mitsudomi, T 2015, 'Collateral chemoresistance to anti- microtubule agents in a lung cancer cell line with acquired resistance to erlotinib', PloS one, vol. 10, no. 4, e0123901. https://doi.org/10.1371/journal.pone.0123901
Mizuuchi, Hiroshi ; Suda, Kenichi ; Sato, Katsuaki ; Tomida, Shuta ; Fujita, Yoshihiko ; Kobayashi, Yoshihisa ; Maehara, Yoshihiko ; Sekido, Yoshitaka ; Nishio, Kazuto ; Mitsudomi, Tetsuya. / Collateral chemoresistance to anti- microtubule agents in a lung cancer cell line with acquired resistance to erlotinib. In: PloS one. 2015 ; Vol. 10, No. 4.
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