Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer.
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.
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; Department of General Internal Medicine 4, Kawasaki Hospital, Kawasaki Medical School, Okayama 700-8505, Japan.
Nobuaki
N
Ochi
Department of General Internal Medicine 4, Kawasaki Hospital, Kawasaki Medical School, Okayama 700-8505, Japan. Electronic address: ntakigaw@med.kawasaki-m.ac.jp.
Nagio
N
Takigawa
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Daijiro
D
Harada
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Masayuki
M
Yasugi
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Eiki
E
Ichihara
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Katsuyuki
K
Hotta
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Masahiro
M
Tabata
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Mitsune
M
Tanimoto
Department of Respiratory Medicine, Okayama University Hospital, Okayama 700-8558, Japan.
Katsuyuki
K
Kiura
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009602:Nitrosamines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D009602:Nitrosamines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D016392:Proto-Oncogene Proteins pp60(c-src); D048049:Extracellular Signal-Regulated MAP Kinases; D000077156:Gefitinib
EGFR; ERK; Gefitinib; Lung cancer; Resistance; Src