Insulin-Like Growth Factor-1 Receptor Inhibition Induces a Resistance Mechanism via the Epidermal Growth Factor Receptor/HER3/AKT Signaling Pathway: Rational Basis for Cotargeting Insulin-Like Growth Factor-1 Receptor and Epidermal Growth Factor Receptor in Hepatocellular Carcinoma
Insulin-Like Growth Factor-1 Receptor Inhibition Induces a Resistance Mechanism via the Epidermal Growth Factor Receptor/HER3/AKT Signaling Pathway: Rational Basis for Cotargeting Insulin-Like Growth Factor-1 Receptor and Epidermal Growth Factor Receptor in Hepatocellular Carcinoma
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DOI：
10.1158/1078-0432.ccr-08-2980
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发表时间：
2009-09-01
影响因子：
11.5
通讯作者：
Rosmorduc, Olivier
中科院分区：
文献类型：
--
作者：
Desbois-Mouthon, Christele;Baron, Aurore;Rosmorduc, Olivier
目的：胰岛素样生长因子（IGF）信号转导轴在肝细胞癌（HCC）中经常失调。因此，我们调查是否特异性靶向的IGF-1型受体（IGF-1 R）可能代表一种新的治疗方法为this tumor.Experimental Design：总的IGF-1 R和磷酸化水平进行了测量，在21对样本的人肝癌和相邻的非肿瘤肝脏使用ELISA。结果：IGF-1 R在33%的肝癌细胞中过表达，52%的肝癌细胞中IGF-1 R的活化增强。AVE 1642单独给药对细胞活力具有中度抑制作用。然而，其与表皮生长因子受体（EGFR）抑制剂吉非替尼的组合在所有细胞系中诱导了与细胞周期阻滞和AKT磷酸化抑制相关的超累加效应。AVE 1642与雷帕霉素的组合还诱导活力和AKT磷酸化的协同降低。值得注意的是，AVE 1642单独上调了HER 3（EGFR的主要配偶体）的磷酸化水平和总水平，吉非替尼阻止了AVE 1642诱导的HER 3磷酸化。结论：肝癌细胞通过激活HER 3克服IGF-1 R抑制是一种EGFR依赖性机制，HER 3是抗IGF-1 R治疗获得性耐药的重要介质。这些结果为在HCC临床试验中同时靶向EGFR和IGF-1 R提供了强有力的理由]。(Clin Cancer Res 2009;15（17）：5445-56）
Purpose: The insulin-like growth factor (IGF) signaling axis is frequently dysregulated in hepatocellular carcinoma (HCC). Therefore, we investigated whether the specific targeting of the IGF type 1 receptor (IGF-1R) might represent a new therapeutic approach for this tumor.Experimental Design: Total and phosphorylated levels of IGF-1R were measured in 21 paired samples of human HCCs and adjacent nontumoral livers using ELISA. The antineoplastic potency of a novel anti-IGF-1R antibody, AVE1642, was examined in five human hepatoma cell lines.Results: Overexpression of IGF-1R was detected in 33% of HCCs and increased activation of IGF-1R was observed in 52% of tumors. AVE1642 alone had moderate inhibitory effects on cell viability. However, its combination with gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, induced supra-additive effects in all cell lines that were associated with cell cycle blockage and inhibition of AKT phosphorylation. The combination of AVE1642 with rapamycin also induced a synergistic reduction of viability and of AKT phosphorylation. Of marked interest, AVE1642 alone up-regulated the phosphorylated and total levels of HER3, the main partner of EGFR, and AVE1642-induced phosphorylation of HER3 was prevented by gefitinib. Moreover, the down-regulation of HER3 expression with siRNA reduced AKT phosphorylation and increased cell sensitivity to AVE1642.Conclusions: These findings indicate that hepatoma cells overcome [GF-1R inhibition through HER3 activation in an EGFR-dependent mechanism, and that HER3 represents a critical mediator in acquired resistance to anti-IGF-1R therapy. These results provide a strong rational for targeting simultaneously EGFR and IGF-1R in clinical trials for HCC]. (Clin Cancer Res 2009;15(17):5445-56)