mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt
mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt
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DOI：
10.1158/0008-5472.can-05-2925
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发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
Rosen, N
中科院分区：
文献类型：
--
作者：
O'Reilly, KE;Rojo, F;Rosen, N
胰岛素和胰岛素样生长因子I（IGF-I）受体的刺激激活磷酸肌醇-3-激酶/Akt/ mTOR途径，引起多效性细胞效应，包括胰岛素受体底物-I表达的mTOR依赖性损失，导致通过该途径的信号传导反馈下调。在模型系统中，表现出磷酸肌醇-3-激酶/Akt激酶的突变激活（癌症中的常见事件）的肿瘤对mTOR抑制剂（包括雷帕霉素）过敏。尽管在模型系统中具有活性，但在患者中，mTOR抑制剂表现出更适度的抗肿瘤活性。我们现在表明，mTOR抑制诱导胰岛素受体底物-I的表达和消除反馈抑制的途径，导致Akt激活在癌细胞系和患者肿瘤治疗的雷帕霉素衍生物，RAD 001。IGF-I受体抑制可防止雷帕霉素诱导的Akt活化，并使肿瘤细胞对mTOR抑制敏感。相反，IGF-I逆转雷帕霉素在无血清培养基中的抗增殖作用。这些数据表明，受体酪氨酸激酶信号传导的反馈下调是具有组成性mTOR激活的肿瘤细胞中的常见事件。雷帕霉素对这种反馈回路的抑制可能会减弱其治疗效果，而消除mTOR功能并防止Akt活化的联合治疗可能具有改善的抗肿瘤活性。
Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/ mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-I expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity. We now show that mTOR inhibition induces insulin receptor substrate-I expression and abrogates feedback inhibition of the pathway, resulting in Akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, RAD001. IGF-I receptor inhibition prevents rapamycin-induced Akt activation and sensitizes tumor cells to inhibition of mTOR. In contrast, IGF-I reverses the antiproliferative effects of rapamycin in serum-free medium. The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation. Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.