title: Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells.
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 EGFR-mutant 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.
authors.affiliation: Department of Thoracic Surgery, Okayama University Hospital, Okayama, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Shien
authors.forename: Shinichi
authors.initials: S
authors.lastname: Toyooka
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Junichi
authors.initials: J
authors.lastname: Soh
authors.forename: Masaru
authors.initials: M
authors.lastname: Jida
authors.forename: Kelsie L
authors.initials: KL
authors.lastname: Thu
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Hashida
authors.forename: Yuho
authors.initials: Y
authors.lastname: Maki
authors.forename: Eiki
authors.initials: E
authors.lastname: Ichihara
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Asano
authors.forename: Kazunori
authors.initials: K
authors.lastname: Tsukuda
authors.forename: Nagio
authors.initials: N
authors.lastname: Takigawa
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Miyoshi
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000077156:Gefitinib; D005838:Genotype; D006801:Humans; D035683:MicroRNAs / Q000032:analysis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014411:Neoplastic Stem Cells; D011799:Quinazolines / Q000494:pharmacology; D050697:Retinal Dehydrogenase; D059467:Transcriptome
chemical_list: C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D011799:Quinazolines; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D066246:ErbB Receptors; D000077156:Gefitinib
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