Insulin-like growth factor-1 receptor (IGF1R) as a novel target in chronic lymphocytic leukemia.
Insulin-like growth factor-1 receptor (IGF1R) as a novel target in chronic lymphocytic leukemia.
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DOI：
10.1182/blood-2013-02-484386
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发表时间：
2013-08
期刊：
影响因子：
20.3
通讯作者：
Niuscha Yaktapour;Rudolf Übelhart;J. Schüler;K. Aumann;C. Dierks;M. Burger;D. Pfeifer;H. Jumaa;H. Veelken;T. Brummer;K. Zirlik
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文献类型：
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作者：
Niuscha Yaktapour;Rudolf Übelhart;J. Schüler;K. Aumann;C. Dierks;M. Burger;D. Pfeifer;H. Jumaa;H. Veelken;T. Brummer;K. Zirlik
受体酪氨酸激酶（RTK）胰岛素样生长因子-1受体（IGF 1 R）与包括慢性淋巴细胞白血病（CLL）在内的各种肿瘤实体有关，但其在这种疾病中的功能意义仍不清楚。在这里，我们表明IGF 1 R蛋白在各种CLL亚群中过表达，这表明对CLL病理学的贡献。事实上，我们表明，IGF 1 R敲低在原代人CLL细胞损害其活力。同样，IGF 1 R抑制与3个结构不同的化合物诱导细胞凋亡，即使在保护性基质成分的存在下。此外，IGF 1 R抑制有效地限制了Eμ-TCL 1转基因小鼠和原代人CLL异种移植物中的CLL发展。与其促生存功能一致，IGF 1 R抑制影响多种信号蛋白的磷酸化和/或表达。多激酶抑制剂索拉非尼对这些信号传导元件产生了与IGF 1 R抑制剂相似的作用。事实上，IGF 1 R似乎是索拉非尼的直接靶点，因为索拉非尼降低了IGF 1 R的表达和磷酸化，抵消了胰岛素样生长因子-1（IGF-1）与CLL细胞的结合，并降低了重组纯化IGF 1 R的体外激酶活性。因此，我们证明了IGF 1 R介导的信号传导的阻断代表了索拉非尼在CLL中的一种新的作用机制。重要的是，IGF 1 R抑制剂在其微环境中损害CLL活力，暗示这种RTK是一种有前途的治疗靶点。
The receptor tyrosine kinase (RTK) insulin-like growth factor-1 receptor (IGF1R) is implicated in various tumor entities including chronic lymphocytic leukemia (CLL), but its functional significance in this disease remains poorly characterized. Here, we show that the IGF1R protein is overexpressed in various CLL subsets, suggesting a contribution to CLL pathology. Indeed, we show that IGF1R knockdown in primary human CLL cells compromised their viability. Likewise, IGF1R inhibition with 3 structurally distinct compounds induced apoptosis, even in the presence of protective stroma components. Furthermore, IGF1R inhibition effectively limited CLL development in Eμ-TCL1 transgenic mice and of primary human CLL xenografts. In agreement with its prosurvival function, IGF1R inhibition affected the phosphorylation and/or expression of multiple signaling proteins. The multikinase inhibitor sorafenib yielded similar effects on these signaling elements as IGF1R inhibitors. Indeed, IGF1R appears to be a direct sorafenib target because sorafenib decreased IGF1R expression and phosphorylation, counteracted insulin-like growth factor-1 (IGF-1) binding to CLL cells, and lowered the in vitro kinase activity of recombinant, purified IGF1R. Thus, we demonstrate that blockade of IGF1R-mediated signaling represents a novel mechanism of action for sorafenib in CLL. Importantly, IGF1R inhibitors compromise CLL viability in their microenvironment context, implicating this RTK as a promising therapeutic target.