Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling.
Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling.
复制标题
PI3K抑制剂快速诱导凋亡取决于它们对Ras-ERK信号传导的短暂抑制。
DOI：
10.1158/2159-8290.cd-13-0611
复制
发表时间：
2014-03
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：
Will M;Qin AC;Toy W;Yao Z;Rodrik-Outmezguine V;Schneider C;Huang X;Monian P;Jiang X;de Stanchina E;Baselga J;Liu N;Chandarlapaty S;Rosen N
The effects of selective PI3K and AKT inhibitors were compared in human tumor cell lines in which the pathway is dysregulated. Both caused inhibition of AKT, relief of feedback inhibition of RTKs, and growth arrest. However, only the PI3K inhibitors caused rapid induction of cell death. In seeking a mechanism for this phenomenon, we found that PI3K inhibition, but not AKT inhibition, causes rapid inhibition of wild type RAS and of RAF/MEK/ERK signaling. Inhibition of RAS-ERK signaling is transient, rebounding a few hours after drug addition, and is required for rapid induction of apoptosis. Combined MEK and AKT inhibition also promotes cell death and in murine models of HER2+ cancer, either pulsatile PI3K inhibition or combined MEK and AKT inhibition causes tumor regressions. We conclude that PI3K is upstream of RAS and AKT and that pulsatile inhibition of both pathways is sufficient for effective antitumor activity.
