Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition.
Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition.
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DOI：
10.1158/1535-7163.mct-08-0668
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发表时间：
2009-04
影响因子：
5.7
通讯作者：
Lane HA
中科院分区：
文献类型：
--
作者：
Breuleux M;Klopfenstein M;Stephan C;Doughty CA;Barys L;Maira SM;Kwiatkowski D;Lane HA
哺乳动物雷帕霉素靶标(MTOR)调节细胞过程，对人类癌症的进展至关重要。RAD001是一种mTORC1(mTOR/Raptor)抑制剂，在临床前模型和癌症患者中具有广泛的抗肿瘤活性。尽管大多数肿瘤细胞系对RAD001敏感，但也有一些不敏感。选择性抑制mTORC1可以诱导AKT S473磷酸化增加，涉及胰岛素受体底物1，这被认为可能减弱对肿瘤细胞增殖和生存的影响。Rictor也可能发挥作用，因为Rictor激酶复合体(包括mTOR/Rictor)调节AKT S473的磷酸化。研究了Raptor和Rictor在人癌细胞对RAD001体外反应中的作用。使用一组代表不同肿瘤组织类型的细胞系，发现AKT S473和一些AKT底物的基础磷酸化与对RAD001的抗增殖反应有关。相反，RAD001诱导的AKT S473磷酸化增加与此无关。在使用siRNA的猛禽耗尽后，AKT磷酸化也出现了类似的增加。值得注意的是，Rictor下调可减弱mTORC1抑制引起的AKT S473磷酸化。进一步分析表明，AKT对S473和T308的磷酸化调控与AKT底物的磷酸化模式无关。使用双PAN-I类磷脂酰肌醇3-激酶/mTOR催化抑制剂(NVP-BEZ235)，目前处于I期试验，同时靶向这些激酶抑制AKT S473磷酸化，引发比单独抑制mTORC1更深刻的细胞反应。然而，细胞活力的降低不能从对mTORC1抑制剂的生化或细胞反应中预测。这些数据可能对磷脂酰肌醇3-激酶/mTOR抑制剂的临床应用有一定的指导意义。
Mammalian target of rapamycin (mTOR) regulates cellular processes important for progression of human cancer. RAD001 (everolimus), an mTORC1 (mTOR/raptor) inhibitor, has broad antitumor activity in preclinical models and cancer patients. Although most tumor lines are RAD001 sensitive, some are not. Selective mTORC1 inhibition can elicit increased AKT S473 phosphorylation, involving insulin receptor substrate 1, which is suggested to potentially attenuate effects on tumor cell proliferation and viability. Rictor may also play a role because rictor kinase complexes (including mTOR/rictor) regulate AKT S473 phosphorylation. The role of raptor and rictor in the in vitro response of human cancer cells to RAD001 was investigated. Using a large panel of cell lines representing different tumor histotypes, the basal phosphorylation of AKT S473 and some AKT substrates was found to correlate with the antiproliferative response to RAD001. In contrast, increased AKT S473 phosphorylation induced by RAD001 did not correlate. Similar increases in AKT phosphorylation occurred following raptor depletion using siRNA. Strikingly, rictor down-regulation attenuated AKT S473 phosphorylation induced by mTORC1 inhibition. Further analyses showed no relationship between modulation of AKT phosphorylation on S473 and T308 and AKTsubstrate phosphorylation patterns. Using a dual pan-class I phosphatidylinositol 3-kinase/mTOR catalytic inhibitor (NVP-BEZ235), currently in phase I trials, concomitant targeting of these kinases inhibited AKT S473 phosphorylation, eliciting more profound cellular responses than mTORC1 inhibition alone. However, reduced cell viability could not be predicted from biochemical or cellular responses to mTORC1 inhibitors. These data could have implications for the clinical application of phosphatidylinositol 3-kinase/mTOR inhibitors.