PMID- 23542356
OWN - NLM
STAT- MEDLINE
DCOM- 20130722
LR  - 20220330
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 73
IP  - 10
DP  - 2013 May 15
TI  - Acquired resistance to EGFR inhibitors is associated with a manifestation of stem 
      cell-like properties in cancer cells.
PG  - 3051-61
LID - 10.1158/0008-5472.CAN-12-4136 [doi]
AB  - 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.
CI  - (c)2013 AACR.
FAU - Shien, Kazuhiko
AU  - Shien K
AD  - Department of Thoracic Surgery, Okayama University Hospital, Okayama, Japan.
FAU - Toyooka, Shinichi
AU  - Toyooka S
FAU - Yamamoto, Hiromasa
AU  - Yamamoto H
FAU - Soh, Junichi
AU  - Soh J
FAU - Jida, Masaru
AU  - Jida M
FAU - Thu, Kelsie L
AU  - Thu KL
FAU - Hashida, Shinsuke
AU  - Hashida S
FAU - Maki, Yuho
AU  - Maki Y
FAU - Ichihara, Eiki
AU  - Ichihara E
FAU - Asano, Hiroaki
AU  - Asano H
FAU - Tsukuda, Kazunori
AU  - Tsukuda K
FAU - Takigawa, Nagio
AU  - Takigawa N
FAU - Kiura, Katsuyuki
AU  - Kiura K
FAU - Gazdar, Adi F
AU  - Gazdar AF
FAU - Lam, Wan L
AU  - Lam WL
FAU - Miyoshi, Shinichiro
AU  - Miyoshi S
LA  - eng
GR  - P50 CA070907/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20130329
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (MIRN200 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Quinazolines)
RN  - EC 1.2.1 (Aldehyde Dehydrogenase 1 Family)
RN  - EC 1.2.1.3 (Aldehyde Dehydrogenase)
RN  - EC 1.2.1.36 (ALDH1A1 protein, human)
RN  - EC 1.2.1.36 (Retinal Dehydrogenase)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Aldehyde Dehydrogenase/genetics
MH  - Aldehyde Dehydrogenase 1 Family
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm
MH  - Epithelial-Mesenchymal Transition
MH  - ErbB Receptors/*antagonists & inhibitors/genetics
MH  - Gefitinib
MH  - Genotype
MH  - Humans
MH  - MicroRNAs/analysis
MH  - Neoplasms/*drug therapy/pathology
MH  - Neoplastic Stem Cells
MH  - Quinazolines/pharmacology
MH  - Retinal Dehydrogenase
MH  - Transcriptome
PMC - PMC4506773
MID - NIHMS707899
COIS- Disclosure of Potential Conflicts of Interest No potential conflicts of interest 
      were disclosed.
EDAT- 2013/04/02 06:00
MHDA- 2013/07/23 06:00
PMCR- 2015/07/19
CRDT- 2013/04/02 06:00
PHST- 2013/04/02 06:00 [entrez]
PHST- 2013/04/02 06:00 [pubmed]
PHST- 2013/07/23 06:00 [medline]
PHST- 2015/07/19 00:00 [pmc-release]
AID - 0008-5472.CAN-12-4136 [pii]
AID - 10.1158/0008-5472.CAN-12-4136 [doi]
PST - ppublish
SO  - Cancer Res. 2013 May 15;73(10):3051-61. doi: 10.1158/0008-5472.CAN-12-4136. Epub 
      2013 Mar 29.