Compensatory Insulin Receptor (IR) Activation on Inhibition of Insulin-Like Growth Factor-1 Receptor (IGF-1R): Rationale for Cotargeting IGF-1R and IR in Cancer
Compensatory Insulin Receptor (IR) Activation on Inhibition of Insulin-Like Growth Factor-1 Receptor (IGF-1R): Rationale for Cotargeting IGF-1R and IR in Cancer
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DOI：
10.1158/1535-7163.mct-10-0318
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发表时间：
2010-10-01
影响因子：
5.7
通讯作者：
Miglarese, Mark R.
中科院分区：
文献类型：
--
作者：
Buck, Elizabeth;Gokhale, Prafulla C.;Miglarese, Mark R.
胰岛素样生长因子-1受体（IGF-1 R）是一种受体酪氨酸激酶（RTK），是磷脂酰肌醇3-激酶-AKT通路的关键激活剂。IGF-1 R是致癌转化和肿瘤发生所必需的。这些观察结果刺激了生物和小分子IGF-1 R抑制剂的抗癌药物发现和开发工作。一种RTK补偿另一种RTK以维持肿瘤细胞活力的能力正在成为靶向个体RTK的抗肿瘤剂的常见耐药机制。由于IGF-1 R在结构和功能上与胰岛素受体（IR）相关，我们询问IR是否具有致瘤性以及IR-AKT信号传导是否有助于抵抗IGF-1 R抑制。IGF-1 R和IR（A）在小鼠乳腺肿瘤模型中均具有致瘤性。在共表达IGF-1 R和IR的人肿瘤细胞中，在敲低IR表达或用选择性抗IGF-1 R抗体MAB 391处理后观察到双向串扰。MAB 391处理导致磷酸-IR的代偿性增加，这与对IRS 1和AKT抑制的抗性相关。相比之下，用OSI-906（IGF-1 R/IR的小分子双重抑制剂）处理导致相对于MAB 391增强的磷酸-IRS 1/磷酸-AKT减少。胰岛素或IGF-2激活IR-AKT通路并降低对MAB 391的敏感性，但不降低对OSI-906的敏感性。在具有自分泌IGF-2环的肿瘤细胞中，OSI-906和抗IGF-2抗体均降低磷酸-IR/磷酸-AKT，而MAB 391无效。最后，OSI-906在IGF-1 R和IR均被磷酸化的人肿瘤异种移植模型中显示出优于MAB 391的功效。总的来说，这些数据表明，与单独靶向IGF-1 R相比，共靶向IGF-1 R和IR可提供上级抗肿瘤功效。Mol Cancer Ther; 9（10）; 2652-64. (C)2010年AACR。
Insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) and critical activator of the phosphatidylinositol 3-kinase-AKT pathway. IGF-1R is required for oncogenic transformation and tumorigenesis. These observations have spurred anticancer drug discovery and development efforts for both biological and small-molecule IGF-1R inhibitors. The ability for one RTK to compensate for another to maintain tumor cell viability is emerging as a common resistance mechanism to antitumor agents targeting individual RTKs. As IGF-1R is structurally and functionally related to the insulin receptor (IR), we asked whether IR is tumorigenic and whether IR-AKT signaling contributes to resistance to IGF-1R inhibition. Both IGF-1R and IR(A) are tumorigenic in a mouse mammary tumor model. In human tumor cells coexpressing IGF-1R and IR, bidirectional cross talk was observed following either knockdown of IR expression or treatment with a selective anti-IGF-1R antibody, MAB391. MAB391 treatment resulted in a compensatory increase in phospho-IR, which was associated with resistance to inhibition of IRS1 and AKT. In contrast, treatment with OSI-906, a small-molecule dual inhibitor of IGF-1R/IR, resulted in enhanced reduction in phospho-IRS1/phospho-AKT relative to MAB391. Insulin or IGF-2 activated the IR-AKT pathway and decreased sensitivity to MAB391 but not to OSI-906. In tumor cells with an autocrine IGF-2 loop, both OSI-906 and an anti-IGF-2 antibody reduced phospho-IR/phospho-AKT, whereas MAB391 was ineffective. Finally, OSI-906 showed superior efficacy compared with MAB391 in human tumor xenograft models in which both IGF-1R and IR were phosphorylated. Collectively, these data indicate that cotargeting IGF-1R and IR may provide superior antitumor efficacy compared with targeting IGF-1R alone. Mol Cancer Ther; 9(10); 2652-64. (C) 2010 AACR.