Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib

Kenichi Suda, Kenji Tomizawa, Makiko Fujii, Hideki Murakami, Hirotaka Osada, Yoshihiko Maehara, Yasushi Yatabe, Yoshitaka Sekido, Tetsuya Mitsudomi

Research output: Contribution to journalArticle

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Abstract

Introduction: Mesenchymal status is related to "inherent resistance" to gefitinib or erlotinib in non-small cell lung cancer without epidermal growth factor receptor(EGFR) mutations. In addition, a recent report showed that the epithelial to mesenchymal transition (EMT) plays a role in acquired resistance to gefitinib in A549 cells, which harbor a KRAS mutation. However, recent clinical studies revealed that gefitinib or erlotinib are highly effective in the treatment of non-small cell lung cancer with EGFR mutations. Methods: We developed resistant cells (HCC4006ER) from erlotinib-sensitive HCC4006 cells harboring an EGFR deletion mutation by chronic exposure to increasing concentrations of erlotinib. Acquired resistance mechanisms of HCC4006ER cells were analyzed. Results: Neither known resistance mechanisms nor novel molecules that may confer erlotinib resistance were identified using candidate or comprehensive analyses. In addition, HCC4006ER cells lost dependency for EGFR. However, we found that HCC4006ER cells acquired a mesenchymal phenotype and exhibited down-regulation of E-cadherin expression (2.7 × 10 times compared with parental cells). We also found that the histone deacetylase inhibitor, MS-275, restored E-cadherin expression and moderate sensitivity to erlotinib in HCC4006ER cells, on the other hand, transforming growth factor beta, an inducer of EMT, led to moderate erlotinib resistance in HCC4006 parental cells. Conclusions: This is the first report of a relationship between EMT and erlotinib acquired resistance in an erlotinib sensitive EGFR-mutant lung cancer cell line. Our results indicate that it would be important to consider the influence of EMT in the development of treatments against acquired resistance to gefitinib or erlotinib.

Original languageEnglish
Pages (from-to)1152-1161
Number of pages10
JournalJournal of Thoracic Oncology
Volume6
Issue number7
DOIs
Publication statusPublished - Jul 2011

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Epithelial-Mesenchymal Transition
Epidermal Growth Factor Receptor
Lung Neoplasms
Cell Line
Cadherins
Non-Small Cell Lung Carcinoma
Mutation
Erlotinib Hydrochloride
Histone Deacetylase Inhibitors
Sequence Deletion
Transforming Growth Factor beta
Down-Regulation
Phenotype

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine

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Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib. / Suda, Kenichi; Tomizawa, Kenji; Fujii, Makiko; Murakami, Hideki; Osada, Hirotaka; Maehara, Yoshihiko; Yatabe, Yasushi; Sekido, Yoshitaka; Mitsudomi, Tetsuya.

In: Journal of Thoracic Oncology, Vol. 6, No. 7, 07.2011, p. 1152-1161.

Research output: Contribution to journalArticle

Suda, K, Tomizawa, K, Fujii, M, Murakami, H, Osada, H, Maehara, Y, Yatabe, Y, Sekido, Y & Mitsudomi, T 2011, 'Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib', Journal of Thoracic Oncology, vol. 6, no. 7, pp. 1152-1161. https://doi.org/10.1097/JTO.0b013e318216ee52
Suda, Kenichi ; Tomizawa, Kenji ; Fujii, Makiko ; Murakami, Hideki ; Osada, Hirotaka ; Maehara, Yoshihiko ; Yatabe, Yasushi ; Sekido, Yoshitaka ; Mitsudomi, Tetsuya. / Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib. In: Journal of Thoracic Oncology. 2011 ; Vol. 6, No. 7. pp. 1152-1161.
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AU - Osada, Hirotaka

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AU - Yatabe, Yasushi

AU - Sekido, Yoshitaka

AU - Mitsudomi, Tetsuya

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AB - Introduction: Mesenchymal status is related to "inherent resistance" to gefitinib or erlotinib in non-small cell lung cancer without epidermal growth factor receptor(EGFR) mutations. In addition, a recent report showed that the epithelial to mesenchymal transition (EMT) plays a role in acquired resistance to gefitinib in A549 cells, which harbor a KRAS mutation. However, recent clinical studies revealed that gefitinib or erlotinib are highly effective in the treatment of non-small cell lung cancer with EGFR mutations. Methods: We developed resistant cells (HCC4006ER) from erlotinib-sensitive HCC4006 cells harboring an EGFR deletion mutation by chronic exposure to increasing concentrations of erlotinib. Acquired resistance mechanisms of HCC4006ER cells were analyzed. Results: Neither known resistance mechanisms nor novel molecules that may confer erlotinib resistance were identified using candidate or comprehensive analyses. In addition, HCC4006ER cells lost dependency for EGFR. However, we found that HCC4006ER cells acquired a mesenchymal phenotype and exhibited down-regulation of E-cadherin expression (2.7 × 10 times compared with parental cells). We also found that the histone deacetylase inhibitor, MS-275, restored E-cadherin expression and moderate sensitivity to erlotinib in HCC4006ER cells, on the other hand, transforming growth factor beta, an inducer of EMT, led to moderate erlotinib resistance in HCC4006 parental cells. Conclusions: This is the first report of a relationship between EMT and erlotinib acquired resistance in an erlotinib sensitive EGFR-mutant lung cancer cell line. Our results indicate that it would be important to consider the influence of EMT in the development of treatments against acquired resistance to gefitinib or erlotinib.

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