PTEN deficiency is associated with reduced sensitivity to mTOR inhibitor in human bladder cancer through the unhampered feedback loop driving PI3K/Akt activation.
PTEN deficiency is associated with reduced sensitivity to mTOR inhibitor in human bladder cancer through the unhampered feedback loop driving PI3K/Akt activation.
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DOI：
10.1038/bjc.2013.505
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发表时间：
2013-09-17
影响因子：
8.8
通讯作者：
Feron, O.
中科院分区：
文献类型：
--
作者：
Seront, E.;Pinto, A.;Bouzin, C.;Bertrand, L.;Machiels, J-P;Feron, O.
临床前研究表明，由于PI3K（磷脂酰肌醇-3激酶）/Akt的激活和mTOR通路的连续刺激，PTEN缺失增强了对哺乳动物雷帕霉素（mTOR）抑制剂靶点的敏感性。然而，在接受mTOR抑制剂依维莫司治疗的晚期移行细胞癌（TCC）患者中，PTEN的丢失与治疗耐药性相关。移行细胞癌标本、人膀胱癌细胞和衍生的小鼠异种移植物被用来评估PTEN状态如何影响mTOR抑制剂的活性。移行细胞癌患者在依维莫司治疗下无进展生存期较短，表现为PTEN缺乏和Akt激活增加。此外，PTEN缺失的膀胱癌细胞对雷帕霉素的敏感性低于表达野生型PTEN的细胞，并且在功能PTEN缺失的情况下，雷帕霉素显著诱导Akt活化。PI3K抑制剂wortmannin对Akt活化的抑制阻断了雷帕霉素诱导的这种反馈回路，从而增强了mTOR抑制剂在体内和体外的抗增殖作用。PTEN缺失后Akt激活的促进作用在mTOR抑制反应中驱动反馈回路的作用可能比促进mTOR通路的作用更突出。这些数据支持使用PI3K和mTOR抑制剂治疗尿路上皮癌，特别是在缺乏功能性PTEN的情况下。
Preclinical studies have shown that PTEN loss enhances sensitivity to mammalian target of Rapamycin (mTOR) inhibitors because of facilitated PI3K (phosphatidylinositol-3 kinase)/Akt activation and consecutive stimulation of the mTOR pathway. In patients with advanced transitional cell carcinoma (TCC) treated with the mTOR inhibitor everolimus, PTEN loss was, however, associated with resistance to treatment. Transitional cell carcinoma specimens, human bladder cancer cells and derived mouse xenografts were used to evaluate how the PTEN status influences the activity of mTOR inhibitors. Transitional cell carcinoma patients with a shorter progression-free survival under everolimus exhibited PTEN deficiency and increased Akt activation. Moreover, PTEN-deficient bladder cancer cells were less sensitive to rapamycin than cells expressing wild-type PTEN, and rapamycin strikingly induced Akt activation in the absence of functional PTEN. Inhibition of Akt activation by the PI3K inhibitor wortmannin interrupted this rapamycin-induced feedback loop, thereby enhancing the antiproliferative effects of the mTOR inhibitor both in vitro and in vivo. Facilitation of Akt activation upon PTEN loss can have a more prominent role in driving the feedback loop in response to mTOR inhibition than in promoting the mTOR pathway. These data support the use of both PI3K and mTOR inhibitors to treat urothelial carcinoma, in particular in the absence of functional PTEN.
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影响因子：
15.8
作者：
Cloughesy, Tim F.;Yoshimoto, Koji;Nghiemphu, Phioanh;Brown, Kevin;Dang, Julie;Zhu, Shaojun;Hsueh, Teli;Chen, Yinan;Wang, Wei;Youngkin, David;Liau, Linda;Martin, Neil;Becker, Don;Bergsneider, Marvin;Lai, Albert;Green, Richard;Oglesby, Tom;Koleto, Michael;Trent, Jeff;Horvath, Steve;Mischel, Paul S.;Mellinghoff, Ingo K.;Sawyers, Charles L.
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
11.4
作者：
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Abraham, RT