Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells

Kazuhiko Shien, Shinichi Toyooka, Hiromasa Yamamoto, Junichi Soh, Masaru Jida, Kelsie L. Thu, Shinsuke Hashida, Yuho Maki, Eiki Ichihara, Hiroaki Asano, Kazunori Tsukuda, Nagio Takigawa, Katsuyuki Kiura, Adi F. Gazdar, Wan L. Lam, Shinichiro Miyosh

Research output: Contribution to journalArticle

181 Scopus citations

Abstract

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) is a critical problem in the treatment of lung cancer. Although several mechanisms have been shown to be responsible for acquired resistance, all mechanisms have not been uncovered. In this study, we investigated the molecular and cellular profiles of the acquired resistant cells to EGFR-TKI in EGFR-mutant lung cancers. Four EGFRmutant cell lines were exposed to gefitinib by stepwise escalation and high-concentration exposure methods, and resistant sublines to gefitinib were established. The molecular profiles and cellular phenotypes of these resistant sublines were characterized. Although previously reported, alterations including secondary EGFR T790M mutation, MET amplification, and appearance of epithelial-to-mesenchymal transition (EMT) features were observed, these 2 drug-exposure methods revealed different resistance mechanisms. The resistant cells with EMT features exhibited downregulation of miRNA-200c by DNA methylation. Furthermore, the HCC827-derived subline characterized by the high-concentration exposure method exhibited not only EMT features but also stem cell-like properties, including aldehyde dehydrogenase isoform 1 (ALDH1A1) overexpression, increase of side-population, and self-renewal capability. Resistant sublines with stem cell-like properties were resistant to conventional chemotherapeutic agents but equally sensitive to histone deacetylase and proteasome inhibitors, compared with their parental cells. ALDH1A1 was upregulated in clinical samples with acquired resistance to gefitinib. In conclusion, our study indicates that the manner of EGFR-TKI exposure influences the mechanism of acquired resistance and the appearance of stem cell-like property with EGFR-TKI treatment. Cancer Res; 73(10); 3051-61.

Original languageEnglish (US)
Pages (from-to)3051-3061
Number of pages11
JournalCancer research
Volume73
Issue number10
DOIs
StatePublished - May 15 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Shien, K., Toyooka, S., Yamamoto, H., Soh, J., Jida, M., Thu, K. L., Hashida, S., Maki, Y., Ichihara, E., Asano, H., Tsukuda, K., Takigawa, N., Kiura, K., Gazdar, A. F., Lam, W. L., & Miyosh, S. (2013). Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells. Cancer research, 73(10), 3051-3061. https://doi.org/10.1158/0008-5472.CAN-12-4136