Induced IGF-1R activation contributes to gefitinib resistance following combined treatment with paclitaxel, cisplatin and gefitinib in A549 lung cancer cells

Abstract

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. IntroductionLung cancer still remains the leading cause of cancer-related mortality in the world, and the majority of patients present with advanced disease at diagnosis or develop recurrence, neither of which is amenable to curative approaches (1). The epidermal growth factor receptor (EGFR) is expressed in a number of tumors, including non-small-cell lung cancer (NSCLC). EGFR is a member of the EGFR family that includes HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4) (2-4). Activation of the EGFR leads to receptor associated tyrosine kinase activity that initiates a cascade of events leading to downstream signaling and a variety of changes characteristic of malignant progression including upregulation of ras, raf, mitogen-activated phosphorylated (MAP) kinase, and phosphatidylinositol 3-kinase (PI3K) and the downstream protein-serine/threonine kinase Akt. In turn, cellular growth and invasive capacity are enhanced. Preclinical data indicate that small molecules that compete with adenosine triphos...

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