Collateral chemoresistance to anti-microtubule agents in a lung cancer cell line with acquired resistance to erlotinib.
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 followi...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4397071?pdf=render |
| _version_ | 1818034283507351552 |
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| author | Hiroshi Mizuuchi Kenichi Suda Katsuaki Sato Shuta Tomida Yoshihiko Fujita Yoshihisa Kobayashi Yoshihiko Maehara Yoshitaka Sekido Kazuto Nishio Tetsuya Mitsudomi |
| author_facet | Hiroshi Mizuuchi Kenichi Suda Katsuaki Sato Shuta Tomida Yoshihiko Fujita Yoshihisa Kobayashi Yoshihiko Maehara Yoshitaka Sekido Kazuto Nishio Tetsuya Mitsudomi |
| author_sort | Hiroshi Mizuuchi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T06:36:42Z |
| format | Article |
| id | doaj.art-8ae20d6a36dc413088e4f991eedd1981 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T06:36:42Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-8ae20d6a36dc413088e4f991eedd19812022-12-22T01:58:55ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01104e012390110.1371/journal.pone.0123901Collateral chemoresistance to anti-microtubule agents in a lung cancer cell line with acquired resistance to erlotinib.Hiroshi MizuuchiKenichi SudaKatsuaki SatoShuta TomidaYoshihiko FujitaYoshihisa KobayashiYoshihiko MaeharaYoshitaka SekidoKazuto NishioTetsuya MitsudomiVarious 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.http://europepmc.org/articles/PMC4397071?pdf=render |
| spellingShingle | Hiroshi Mizuuchi Kenichi Suda Katsuaki Sato Shuta Tomida Yoshihiko Fujita Yoshihisa Kobayashi Yoshihiko Maehara Yoshitaka Sekido Kazuto Nishio Tetsuya Mitsudomi Collateral chemoresistance to anti-microtubule agents in a lung cancer cell line with acquired resistance to erlotinib. PLoS ONE |
| title | Collateral chemoresistance to anti-microtubule agents in a lung cancer cell line with acquired resistance to erlotinib. |
| title_full | Collateral chemoresistance to anti-microtubule agents in a lung cancer cell line with acquired resistance to erlotinib. |
| title_fullStr | Collateral chemoresistance to anti-microtubule agents in a lung cancer cell line with acquired resistance to erlotinib. |
| title_full_unstemmed | Collateral chemoresistance to anti-microtubule agents in a lung cancer cell line with acquired resistance to erlotinib. |
| title_short | Collateral chemoresistance to anti-microtubule agents in a lung cancer cell line with acquired resistance to erlotinib. |
| title_sort | collateral chemoresistance to anti microtubule agents in a lung cancer cell line with acquired resistance to erlotinib |
| url | http://europepmc.org/articles/PMC4397071?pdf=render |
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