蛋白激酶B
受体酪氨酸激酶
mTORC1型
癌症研究
磷酸化
信号转导
PI3K/AKT/mTOR通路
酪氨酸激酶
化学
细胞生物学
生物
ROR1型
受体
血小板源性生长因子受体
生物化学
生长因子
作者
Sarat Chandarlapaty,Ayana Sawai,Maurizio Scaltriti,Vanessa Rodrik-Outmezguine,Olivera Grbovic-Huezo,Violeta Serra,Pradip K. Majumder,José Baselga,Neal Rosen
出处
期刊:Cancer Cell
[Elsevier]
日期:2011-01-01
卷期号:19 (1): 58-71
被引量:854
标识
DOI:10.1016/j.ccr.2010.10.031
摘要
Activation of the PI3K-AKT pathway in tumors is modulated by negative feedback, including mTORC1-mediated inhibition of upstream signaling. We now show that AKT inhibition induces the expression and phosphorylation of multiple receptor tyrosine kinases (RTKs). In a wide spectrum of tumor types, inhibition of AKT induces a conserved set of RTKs, including HER3, IGF-1R, and insulin receptor. This is in part due to mTORC1 inhibition and in part secondary to a FOXO-dependent activation of receptor expression. PI3K-AKT inhibitors relieve this feedback and activate RTK signaling; this may attenuate their antitumor activity. Consistent with this model, we find that, in tumors in which AKT suppresses HER3 expression, combined inhibition of AKT and HER kinase activity is more effective than either alone.
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