The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients.
The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients.
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DOI：
10.18632/oncotarget.114
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发表时间：
2010-06
期刊：
影响因子：
--
通讯作者：
McCubrey JA
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文献类型：
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作者：
Martelli AM;Evangelisti C;Chiarini F;McCubrey JA
磷脂酰肌醇3-激酶(PI3K)/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）信号轴在生理条件下细胞增殖、生长和存活中起核心作用。然而，异常的PI3K/Akt/mTOR信号传导与许多人类癌症有关，包括急性髓性白血病（AML）。因此，PI3K/Akt/mTOR网络被认为是创新癌症治疗的有效靶点。急性髓性白血病已达到标准多重化疗的可接受毒性极限。因此需要新的治疗策略。这篇综述强调了PI3K/Akt/mTOR信号轴在AML患者中是如何组成性活跃的，它影响白血病细胞（包括白血病干细胞）的存活、增殖和耐药性。单独使用或与其他药物联合使用的小分子激酶抑制剂有效靶向这一途径可能导致白血病细胞生长的抑制。此外，使用小药理学抑制剂靶向PI3K/Akt/mTOR信号网络，无论是单独使用还是与其他药物联合使用，都可能导致对AML患者毒性更小且更有效的治疗。目前正在努力开发PI3K/Akt/mTOR级联抑制剂，这些抑制剂在临床环境中显示出有效性和安全性。
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling axis plays a central role in cell proliferation, growth, and survival under physiological conditions. However, aberrant PI3K/Akt/mTOR signaling has been implicated in many human cancers, including acute myelogenous leukemia (AML). Therefore, the PI3K/Akt/mTOR network is considered as a validated target for innovative cancer therapy. The limit of acceptable toxicity for standard polychemotherapy has been reached in AML. Novel therapeutic strategies are therefore needed. This review highlights how the PI3K/Akt/mTOR signaling axis is constitutively active in AML patients, where it affects survival, proliferation, and drug-resistance of leukemic cells including leukemic stem cells. Effective targeting of this pathway with small molecule kinase inhibitors, employed alone or in combination with other drugs, could result in the suppression of leukemic cell growth. Furthermore, targeting the PI3K/Akt/mTOR signaling network with small pharmacological inhibitors, employed either alone or in combinations with other drugs, may result in less toxic and more efficacious treatment of AML patients. Efforts to exploit pharmacological inhibitors of the PI3K/Akt/mTOR cascade which show efficacy and safety in the clinical setting are now underway.