Delineating the mTOR Kinase Pathway Using a Dual TORC1/2 Inhibitor, AZD8055, in Multiple Myeloma
Delineating the mTOR Kinase Pathway Using a Dual TORC1/2 Inhibitor, AZD8055, in Multiple Myeloma
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DOI：
10.1158/1535-7163.mct-14-0147
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发表时间：
2014-11-01
影响因子：
5.7
通讯作者：
Raje, Noopur
中科院分区：
文献类型：
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作者：
Cirstea, Diana;Santo, Loredana;Raje, Noopur
尽管mTOR激酶抑制剂治疗多发性骨髓瘤的临床前结果很有希望，但对这些药物的耐药性可能是通过反馈激活回路产生的。这种担忧对于胰岛素样生长因子1受体（IGF1R）尤其如此，因为IGF1R信号被AKT和mTOR的多种反馈机制下调。我们使用新型选择性mTOR激酶抑制剂AZD8055在多发性骨髓瘤中验证了这一假设。在AZD8055或雷帕霉素抑制mTOR的情况下，我们评估了p-mTOR S-2481作为多发性骨髓瘤细胞中mTORC2/Akt活性的读取值。接下来，我们验证了AZD8055在多发性骨髓瘤细胞单独或骨髓基质细胞和生长因子培养中对mTORC1和mTORC2功能的抑制作用。与雷帕霉素不同，AZD8055导致多发性骨髓瘤细胞凋亡。然而，AZD8055处理诱导表达p-Akt s -473的多发性骨髓瘤细胞系中IGF1R磷酸化上调。此外，azd8055处理的细胞暴露于IGF1诱导p-Akt S-473，并使多发性骨髓瘤细胞免于凋亡，尽管mTOR激酶抑制和TORC2/Akt阻断。阻断IGF1R抗体的加入逆转了这种作用，并增加了azd8055诱导的细胞凋亡。我们的研究表明，AZD8055和IGF1R阻断药物联合治疗具有IGF1R/Akt信号介导的多发性骨髓瘤是一种很有前景的治疗策略。(c) 2014年aacr。
Despite promising preclinical results with mTOR kinase inhibitors in multiple myeloma, resistance to these drugs may arise via feedback activation loops. This concern is especially true for insulin-like growth factor 1 receptor (IGF1R), because IGF1R signaling is downregulated by multiple AKT and mTOR feedback mechanisms. We have tested this hypothesis in multiple myeloma using the novel selective mTOR kinase inhibitor AZD8055. We evaluated p-mTOR S-2481 as the readout for mTORC2/Akt activity in multiple myeloma cells in the context of mTOR inhibition via AZD8055 or rapamycin. We next validated AZD8055 inhibition of mTORC1 and mTORC2 functions in multiple myeloma cells alone or in culture with bone marrow stroma cells and growth factors. Unlike rapamycin, AZD8055 resulted in apoptosis of multiple myeloma cells. AZD8055 treatment, however, induced upregulation of IGF1R phosphorylation in p-Akt S-473-expressing multiple myeloma cell lines. Furthermore, exposure of AZD8055-treated cells to IGF1 induced p-Akt S-473 and rescued multiple myeloma cells from apoptosis despite mTOR kinase inhibition and TORC2/Akt blockage. The addition of blocking IGF1R antibody resulted in reversing this effect and increased AZD8055-induced apoptosis. Our study suggests that combination treatment with AZD8055 and IGF1R-blocking agents is a promising strategy in multiple myeloma with potential IGF1R/Akt signaling-mediated survival. (C) 2014 AACR.