文章：

选择性靶向mTORC1/2蛋白激酶复合物导致体外和体内的抗白血病作用

Selective targeting of the mTORC1/2 protein kinase complexes leads to antileukemic effects in vitro and in vivo

原文发布日期：2011-09-02

DOI: 10.1038/bcj.2011.30

类型: Original Article

开放获取: 是

英文摘要：

The BCR/ABL tyrosine kinase promotes leukemogenesis through activation of several targets that include the phosphoinositide 3-kinase (PI3K). Tyrosine kinase inhibitors (TKIs), which target BCR/ABL, induce striking clinical responses. However, therapy with TKIs is associated with limitations such as drug intolerance, inability to universally eradicate the disease and emergence of BCR/ABL drug-resistant mutants. To overcome these limitations, we tested whether inhibition of the PI3K/target of rapamycin (mTOR) signaling pathway has antileukemic effect in primary hematopoietic stem cells and BA/F3 cells expressing the BCR/ABL oncoprotein. We determined that dual inhibition of PI3K/mTOR causes growth arrest and apoptosis leading to profound antileukemic effects both in vitro and in vivo. We also established that pharmacologic inhibition of the mTORC1/mTORC2 complexes is sufficient to cause these antileukemic effects. Our results support the development of inhibitors of the mTORC1/2 complexes for the therapy of leukemias that either express BCR/ABL or display deregulation of the PI3K/mTOR signaling pathway.

摘要翻译： 

BCR/ABL酪氨酸激酶通过激活包括磷脂酰肌醇3-激酶（PI3K）在内的多个靶点促进白血病发生。靶向BCR/ABL的酪氨酸激酶抑制剂（TKIs）能引发显著的临床应答，但其治疗存在局限性：药物不耐受、无法普适性根除疾病，以及BCR/ABL耐药突变体的出现。为突破这些局限，我们通过实验验证抑制PI3K/雷帕霉素靶蛋白（mTOR）信号通路是否对表达BCR/ABL癌蛋白的原代造血干细胞及BA/F3细胞具有抗白血病效应。研究发现，PI3K/mTOR双重抑制剂可通过诱导生长停滞与细胞凋亡，在体外和体内均产生显著抗白血病作用。同时证实mTORC1/mTORC2复合物的药理抑制足以引发这些抗白血病效应。本研究为开发mTORC1/2复合物抑制剂治疗BCR/ABL阳性或PI3K/mTOR信号通路失调的白血病提供了理论依据。

原文链接：

Selective targeting of the mTORC1/2 protein kinase complexes leads to antileukemic effects in vitro and in vivo