Efficacy of and resistance to anti-IGF-1R therapies in Ewing's sarcoma is dependent on insulin receptor signaling
Efficacy of and resistance to anti-IGF-1R therapies in Ewing's sarcoma is dependent on insulin receptor signaling
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DOI：
10.1038/onc.2010.640
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发表时间：
2011-06-01
期刊：
影响因子：
8
通讯作者：
Scotlandi, K.
中科院分区：
文献类型：
--
作者：
Garofalo, C.;Manara, M. C.;Scotlandi, K.
确定患者选择标准和了解耐药发生的潜在机制，对于抗胰岛素样生长因子（IGF）-1R疗法临床试验的适当和成功设计至关重要。很少有尤文氏肉瘤对IGF-1 R靶向高度敏感，了解原因可能是改善成功治疗的秘密。在本文中，我们表明，一个主要的机制，抵抗高度特异性的IGF-1 R抑制剂，无论是抗体或酪氨酸激酶抑制剂可能涉及增强胰岛素受体（IR）-A同型二聚体的形成和IGF-2的生产。耐药细胞能够从IGF-1/IGF-1 R转换为IGF-2/伊拉依赖，以维持AKT和ERK 1/2的持续激活、增殖、迁移和转移。这些细胞还对胰岛素表现出更高的增殖反应，这与维持增殖和恶性肿瘤而不是代谢的胰岛素途径的转变一致。我们的研究结果表明IR-A在引发抗IGF-1 R治疗的内在和适应性抗性中的作用。因此，我们指出，低IGF-1 R：IR比例的肿瘤不太可能从抗IGF-1 R治疗中获益，抗IGF-1 R治疗的疗效应与癌细胞中的伊拉：IGF-1 R比例相关。此外，我们提供的证据支持IR-A作为肉瘤治疗的重要靶点。Oncogene（2011）30，2730-2740; doi：10.1038/onc.2010.640; 2011年1月31日在线发表
Identification of patient selection criteria and understanding of the potential mechanisms involved in the development of resistance are crucial for an appropriate and successful design of clinical trials with anti-insulinlike growth factor (IGF)-1R therapies. Few Ewing's sarcomas are highly sensitive to IGF-1R targeting and understanding the reason why, may hold the secret to improve successful treatments. In this paper, we show that a major mechanism of resistance to highly specific inhibitors of IGF-1R, either antibodies or tyrosine kinase inhibitors may involve enhanced insulin receptor (IR)-A homodimer formation and IGF-2 production. Resistant cells are able to switch from IGF-1/IGF-1R to IGF-2/IRA dependency to maintain sustained activation of AKT and ERK1/2, proliferation, migration and metastasis. These cells also showed higher proliferative response to insulin, in keeping with a switch towards insulin pathways sustaining proliferation and malignancy, rather than metabolism. Our findings demonstrate a role for IR-A in eliciting intrinsic and adaptive resistance to anti-IGF-1R therapies. Thus, we indicate that tumors with low IGF1R: IR ratio are unlikely to greatly benefit from anti-IGF1R therapies and that the efficacy of anti-IGF-1R therapies should be evaluated in relationship to the IRA: IGF-1R ratio in cancer cells. Moreover, we provide evidences supporting IR-A as an important target in sarcoma therapy. Oncogene (2011) 30, 2730-2740; doi: 10.1038/onc.2010.640; published online 31 January 2011