title: Induced IGF-1R activation contributes to gefitinib resistance following combined treatment with paclitaxel, cisplatin and gefitinib in A549 lung cancer cells.
abstract: Gefitinib demonstrates excellent performance in the treatment of lung adenocarcinoma patients; yet, there was no added benefit in combination with chemotherapy as reported in a phase III clinical trial. For exploring the mechanism of the failed combination therapy in lung cancer, in the present study, four therapy assessment groups, including a control group, a chemotherapy group [paclitaxel+cisplatin (TP)], a gefitinib monotherapy group (G) and a combination group[paclitaxel+cisplatin+gefitinib (TP+G)], were established in an A549 cell line and mouse xenotransplanted tumor models.By HPLC, we found that the gefitinib concentration was significantly higher in the combination group when compared to that in the G group in the non-small cell lung cancer cell line, A549 (p<0.05). Following the treatment time extension,an increased cell growth rate was observed in the combination group, while the cellular concentration of gefitinib was not decreased. The expression levels of P-IGF-1R, P-SRC and P-ERK in the fourth combination treatment group were significantly higher than levels in the fourth G treatment and control groups (p<0.05). Following downregulating of IGF-1R in the fourth combination treatment group, drug sensitivity was recovered in vitro. In the mouse model, compared with the gefitinib monotherapy group, the combination group exhibited a smaller tumor volume, lower body weight and reduced survival rate (p<0.05). Gefitinib concentrations in the serum and tumor tissues in the combination therapy group were also decreased when compared with these concentrations in the gefitinib alone group. The present study is the first to demonstrate that the decreased gefitinib concentration in serum and tumor tissues is one of the reasons resulting in the failed combination treatment (chemotherapy+gefitinib) in vivo study. Frequent use of the combination treatment in A549 lung cancer cells induced IGF-1R activation which contributed to gefitinib resistance and gave rise to the failure of the combination therapy.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Ge
authors.forename: Qingjuan
authors.initials: Q
authors.lastname: Chen
authors.forename: Yang Ping
authors.initials: YP
authors.lastname: Wu
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hongwei
authors.initials: H
authors.lastname: Xia
authors.forename: Dandan
authors.initials: D
authors.lastname: Yuan
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Weibing
authors.initials: W
authors.lastname: Leng
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Qiulin
authors.initials: Q
authors.lastname: Tang
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Pang
authors.forename: Feng
authors.initials: F
authors.lastname: Bi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics*; D017211:Treatment Failure; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: C000597236:IGF1R protein, human; D011799:Quinazolines; D017451:Receptors, Somatomedin; D017526:Receptor, IGF Type 1; D017239:Paclitaxel; D002945:Cisplatin; D000077156:Gefitinib