Optimal targeting of the mTORC1 kinase in human cancer
Optimal targeting of the mTORC1 kinase in human cancer
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DOI：
10.1016/j.ceb.2009.01.016
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发表时间：
2009-04-01
影响因子：
7.5
通讯作者：
Breuleux, Madlaina
中科院分区：
文献类型：
--
作者：
Lane, Heidi A.;Breuleux, Madlaina
哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）激酶是生长因子、营养物质和能量来源的重要传感器，在肿瘤生物学中起着关键作用。因此，mTORC 1抑制剂在临床前实验肿瘤模型中以及临床上癌症患者中显示出广泛的抗肿瘤活性。引人注目的是，某些肿瘤类型似乎倾向于对mTORC 1抑制作出反应，这是一种与PI 3 K/mTORC 1通路的关键元件失调相关的现象。在这篇综述中，我们讨论了mTORC 1肿瘤诱导的生存途径激活的背景下，参与恶性转化的不同信号传导模块之间的串扰，合理的目标组合方案的定义和生物学为基础的剂量和患者分层策略的临床开发的优化。在可能的情况下，强调基于完整临床出版物的mTORC 1药物开发决策。
A central sensor of the availability of growth factors, nutrients and energy sources, the mammalian target of rapamycin complex 1 (mTORC1) kinase plays a key role in tumor biology. Consequently, mTORC1 inhibitors have been shown to have broad antitumor activity pre-clinically in experimental tumor models as well as clinically in cancer patients. Strikingly, certain tumor types appear to be predisposed to respond to mTORC1 inhibition, a phenomenon related to deregulation of critical elements of the PI3K/mTORC1 pathway. In this review we address optimization of clinical development in the context of mTORC1 inhibitor-induced activation of survival pathways, crosstalk between different signaling modules involved in malignant transformation, definition of rational target combination scenarios and biologically based dosing and patient stratification strategies. Emphasis is given where possible to mTORC1 drug development decisions based on full clinical publications.