Downregulation of IGFBP2 is associated with resistance to IGF1R therapy in rhabdomyosarcoma.
Downregulation of IGFBP2 is associated with resistance to IGF1R therapy in rhabdomyosarcoma.
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作者：
Kang Z;Yu Y;Zhu YJ;Davis S;Walker R;Meltzer PS;Helman LJ;Cao L
靶向胰岛素样生长因子-1受体（IGF 1 R）的药物正在临床开发中，但是，尽管在肉瘤中单一药物取得了一些初步成功，但反应率较低且持续时间较短。因此，重要的是要确定预测反应的标志物，了解耐药机制，并探索联合治疗。在这项研究中，我们发现，尽管与PAX 3-FKHR易位相关，但IGF 1 R水平升高是总生存率较差的独立预后标志物，特别是在PAX 3-FKHR阳性横纹肌肉瘤（RMS）患者中。使用体内模型产生IGF 1 R抗体抗性RMS细胞。表达分析表明，IGFBP 2是胰岛素样生长因子（IGF）信号通路中受影响最大的基因，也是耐药株中下调最显著的基因，表明在对IGF 1 R抗体耐药的肿瘤细胞中存在抑制IGFBP 2表达的强选择性。IGFBP 2抑制IGF 1 R磷酸化及其信号传导。与IGF 1/2或IGF 2抗体类似，外源性IGFBP 2的加入增强了IGF 1 R抗体对RMS细胞的活性，并逆转了对IGF 1 R抗体的抗性。与IGF 1 R相反，IGFBP 2的较低表达与较差的总生存期相关，与本研究中发现的其抑制活性一致。最后，用磷脂酰肌醇3-激酶（PI 3 K）或雷帕霉素的哺乳动物靶蛋白（mTOR）特异性抑制剂阻断下游蛋白激酶B（AKT）活化显著地使抗性细胞对IGF 1 R抗体敏感。这些发现表明，组成型IGFBP 2下调可能代表了体内对IGF 1 R治疗性抗体获得性抗性的新机制，并提示了各种药物组合以增强抗体活性和克服抗性。
Agents targeting the insulin-like growth factor-1 receptor (IGF1R) are in clinical development, but, despite some initial success of single agents in sarcoma, response rates are low with brief durations. Thus, it is important to identify markers predictive of response, to understand mechanisms of resistance, and to explore combination therapies. In this study, we found that, although associated with PAX3-FKHR translocation, increased IGF1R level is an independent prognostic marker for worse overall survival, particularly in patients with PAX3-FKHR-positive rhabdomyosarcoma (RMS). IGF1R antibody-resistant RMS cells were generated using an in vivo model. Expression analysis indicated that IGFBP2 is both the most affected gene in the insulin-like growth factor (IGF) signaling pathway and the most significantly downregulated gene in the resistant lines, indicating that there is a strong selection to repress IGFBP2 expression in tumor cells resistant to IGF1R antibody. IGFBP2 is inhibitory to IGF1R phosphorylation and its signaling. Similar to antibodies to IGF1/2 or IGF2, the addition of exogenous IGFBP2 potentiates the activity of IGF1R antibody against the RMS cells, and it reverses the resistance to IGF1R antibody. In contrast to IGF1R, lower expression of IGFBP2 is associated with poorer overall survival, consistent with its inhibitory activity found in this study. Finally, blocking downstream Protein kinase B (AKT) activation with Phosphatidylinositide 3-kinases (PI3K)- or mammalian target of rapamycin (mTOR)-specific inhibitors significantly sensitized the resistant cells to the IGF1R antibody. These findings show that constitutive IGFBP2 downregulation may represent a novel mechanism for acquired resistance to IGF1R therapeutic antibody in vivo and suggest various drug combinations to enhance antibody activity and to overcome resistance.
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