Document Detail


Hypoxia induces gefitinib resistance in non-small-cell lung cancer with both mutant and wild-type epidermal growth factor receptors.
MedLine Citation:
PMID:  22863020     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Somatic mutations in the epidermal growth factor receptor (EGFR) gene, such as exon 19 deletion mutations, are important factors in determining therapeutic responses to gefitinib in non-small-cell lung cancer (NSCLC). However, some patients have activating mutations in EGFR and show poor responses to gefitinib. In this study, we examined three NSCLC cell lines, HCC827, PC9, and HCC2935, that expressed an EGFR exon 19 deletion mutation. All cells expressed mutant EGFR, but the PC9 and HCC2935 cells also expressed wild-type EGFR. The HCC827 cells were highly sensitive to gefitinib under both normoxia and hypoxia. However, the PC9 and HCC2935 cells were more resistant to gefitinib under hypoxic conditions compared to normoxia. Phosphorylation of EGFR and ERK was suppressed with gefitinib treatment to a lesser extent under hypoxia. The expression of transforming growth factor-α (TGFα) was dramatically upregulated under hypoxia, and the knockdown of TGFα or hypoxia-inducible factor-1α (HIF1α) reversed the resistance to gefitinib in hypoxic PC9 and HCC2935 cells. Finally, introduction of the wild-type EGFR gene into the HCC827 cells caused resistance to gefitinib under hypoxia. This phenomenon was also reversed by the knockdown of TGFα or HIF1α. Our results indicate that hypoxia causes gefitinib resistance in EGFR-mutant NSCLC through the activation of wild-type EGFR mediated by the upregulation of TGFα. The presence of wild-type and mutant EGFR along with tumor hypoxia are important factors that should be considered when treating NSCLC patients with gefitinib.
Authors:
Kunihiko Minakata; Fumiyuki Takahashi; Takeshi Nara; Muneaki Hashimoto; Ken Tajima; Akiko Murakami; Fariz Nurwidya; Suzu Yae; Fumiaki Koizumi; Hiroyuki Moriyama; Kuniaki Seyama; Kazuto Nishio; Kazuhisa Takahashi
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-09-14
Journal Detail:
Title:  Cancer science     Volume:  103     ISSN:  1349-7006     ISO Abbreviation:  Cancer Sci.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-30     Completed Date:  2013-03-28     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  101168776     Medline TA:  Cancer Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  1946-54     Citation Subset:  IM    
Copyright Information:
© 2012 Japanese Cancer Association.
Affiliation:
Department of Respiratory Medicine, Juntendo University, Tokyo, Japan.
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MeSH Terms
Descriptor/Qualifier:
Carcinoma, Non-Small-Cell Lung / drug therapy*,  genetics,  metabolism*,  pathology
Cell Hypoxia / physiology*
Cell Line, Tumor
Drug Resistance, Neoplasm
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics,  metabolism
Lung Neoplasms / drug therapy*,  genetics,  metabolism,  pathology*
MAP Kinase Signaling System / drug effects,  genetics
Mutation
Phosphorylation / drug effects,  genetics
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-akt / genetics,  metabolism
Quinazolines / pharmacology*
Receptor, Epidermal Growth Factor / antagonists & inhibitors,  genetics*,  metabolism
Transforming Growth Factor alpha / genetics,  metabolism
Up-Regulation / drug effects,  genetics
Chemical
Reg. No./Substance:
0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Protein Kinase Inhibitors; 0/Quinazolines; 0/Transforming Growth Factor alpha; EC 2.7.10.1/EGFR protein, human; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; S65743JHBS/gefitinib

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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