Hypoxia induces gefitinib resistance in non-small-cell lung cancer with both mutant and wild-type epidermal growth factor receptors
| Autor: | Kunihiko Minakata, Hiroyuki Moriyama, Muneaki Hashimoto, Kuniaki Seyama, Takeshi Nara, Kazuto Nishio, Fumiyuki Takahashi, Kazuhisa Takahashi, Suzu Yae, Fariz Nurwidya, Fumiaki Koizumi, Akiko Murakami, Ken Tajima |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
TGF alpha Lung Neoplasms MAP Kinase Signaling System Biology Gefitinib Epidermal growth factor Carcinoma Non-Small-Cell Lung Cell Line Tumor medicine Humans Epidermal growth factor receptor Phosphorylation skin and connective tissue diseases Protein Kinase Inhibitors neoplasms Gene knockdown Tumor hypoxia Original Articles General Medicine Transforming Growth Factor alpha Hypoxia-Inducible Factor 1 alpha Subunit Cell Hypoxia Up-Regulation respiratory tract diseases EGFR Exon 19 Deletion Mutation ErbB Receptors Oncology Drug Resistance Neoplasm Mutation Quinazolines Cancer research biology.protein Proto-Oncogene Proteins c-akt medicine.drug Transforming growth factor |
| Zdroj: | Cancer Sci |
| ISSN: | 1347-9032 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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