mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling.
mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling.
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DOI：
10.1158/2159-8290.cd-11-0085
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发表时间：
2011-08
期刊：
影响因子：
28.2
通讯作者：
Rosen N
中科院分区：
文献类型：
--
作者：
Rodrik-Outmezguine VS;Chandarlapaty S;Pagano NC;Poulikakos PI;Scaltriti M;Moskatel E;Baselga J;Guichard S;Rosen N
mTOR激酶抑制剂阻断mTORC1和mTORC2，因此不会引起雷帕霉素对AKT的mTORC2激活。然而，我们现在表明，这些药物对AKT有双相作用。抑制mTORC2可导致AKT S473去磷酸化，并快速但短暂地抑制AKT T308磷酸化和AKT信号传导。然而，mTOR激酶的抑制也减轻了rtk的反馈抑制，导致随后的PI3K激活和AKT T308的再磷酸化，足以重新激活AKT的活性和信号传导。因此，mTOR激酶的催化抑制导致了一个新的稳态，其特征是mTORC1的深度抑制和T308而不是S473磷酸化的活化AKT的积累。联合抑制mTOR激酶和诱导的RTKs完全消除AKT信号，导致体内细胞深度死亡和肿瘤消退。这些发现揭示了致癌信号网络的自适应能力以及单药抑制反馈调节通路的局限性。
mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT S473 dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. However, inhibition of mTOR kinase also relieves feedback inhibition of RTKs leading to subsequent PI3K activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound inhibition of mTORC1 and accumulation of activated AKT phosphorylated on T308 but not S473. Combined inhibition of mTOR kinase and the induced RTKs fully abolishes AKT signaling and results in profound cell death and tumor regression in vivo. These findings reveal the adaptive capabilities of oncogenic signaling networks and the limitations of monotherapy for inhibiting feedback-regulated pathways.