| Hypoxia Induces Gefitinib Resistance in Non-Small Cell Lung Cancer with Both Mutant and Wild-type Epidermal Growth Factor Receptors. | |
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MedLine Citation:
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PMID: 22863020 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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 exhibit poor responses to gefitinib. In this study, we examined 3 NSCLC cell lines, HCC827, PC9, and HCC2935, which expressed an EGFR exon 19 deletion mutation. While the HCC827 cells expressed only mutant EGFR, the PC9 and HCC2935 cells expressed not only mutant EGFR but also wild-type EGFR. The HCC827 cells were highly sensitive to gefitinib under both normoxia and hypoxia. However, the hypoxic PC9 and HCC2935 cells were more resistant to gefitinib compared to those under 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 the 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. |
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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2012-8-6 |
Journal Detail:
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Title: Cancer science Volume: - ISSN: 1349-7006 ISO Abbreviation: Cancer Sci. Publication Date: 2012 Aug |
Date Detail:
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Created Date: 2012-8-6 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101168776 Medline TA: Cancer Sci Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2012 Japanese Cancer Association. |
Affiliation:
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Department of Respiratory Medicine, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan; Research Institute for Diseases of Old Ages, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan. |
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