Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer |
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Authors: | Nobuaki Ochi Nagio Takigawa Daijiro Harada Masayuki Yasugi Eiki Ichihara Katsuyuki Hotta Masahiro Tabata Mitsune Tanimoto Katsuyuki Kiura |
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Affiliation: | 1. Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan;2. Department of General Internal Medicine 4, Kawasaki Hospital, Kawasaki Medical School, Okayama 700-8505, Japan;3. Department of Respiratory Medicine, Okayama University Hospital, Okayama 700-8558, Japan |
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Abstract: | To study epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance mechanisms, we established a novel gefitinib-resistant lung cancer cell line derived from an EGFR-mutant non-small cell lung cancer cell line (PC-9) pretreated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (designated PC9-GR). We found that gefitinib substantially suppressed the EGFR signaling pathway, whereas ERK was reactivated after several hours in PC9-GR but not in PC-9. The combination of gefitinib with ERK inhibition (by U0126) restored gefitinib susceptibility in PC9-GR, but PI3K-Akt inhibition with LY294002 did not. Although the levels of phosphorylated Src were up-regulated simultaneously with ERK reactivation, neither ERK suppression using U0126 nor an ERK-specific siRNA induced Src phosphorylation. Furthermore, dual inhibition of EGFR and Src restored gefitinib sensitivity in PC9-GR in vitro and in vivo. In conclusion, our results indicate that Src-mediated ERK reactivation may play a role in a novel gefitinib resistance mechanism, and that the combined use of gefitinib with a Src inhibitor may be a potent strategy to overcome this resistance. |
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Keywords: | EGFR, epidermal growth factor receptor ERK, extracellular signal-regulated kinase IGF-1R, insulin-like growth factor-1 receptor MAPK, mitogen-activated protein kinase MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone NSCLC, non-small cell lung cancer PI, propidium iodide PTEN, phosphatase and tensin homolog siRNA, small interfering RNA TKI, tyrosine kinase inhibitor |
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