A genetic mouse model of invasive endometrial cancer driven by concurrent loss of Pten and Lkb1 Is highly responsive to mTOR inhibition.
A genetic mouse model of invasive endometrial cancer driven by concurrent loss of Pten and Lkb1 Is highly responsive to mTOR inhibition.
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DOI：
10.1158/0008-5472.can-13-0544
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发表时间：
2014-01-01
期刊：
影响因子：
11.2
通讯作者：
Zhao JJ
中科院分区：
文献类型：
--
作者：
Cheng H;Liu P;Zhang F;Xu E;Symonds L;Ohlson CE;Bronson RT;Maira SM;Di Tomaso E;Li J;Myers AP;Cantley LC;Mills GB;Zhao JJ
来自肿瘤抑制因子 PTEN 和 LKB1 的信号汇聚到 mTOR 上，负向调节其在癌细胞中的功能。值得注意的是，这两种抑制剂在大部分人类子宫内膜肿瘤中均减弱。在这项研究中，我们建立了一个由这些抑制因子同时丢失驱动的子宫内膜癌遗传小鼠模型，以获得对该疾病的病理生理学了解。子宫内膜上皮中 Pten 和 Lkb1 的双重缺失导致晚期子宫内膜样子宫内膜肿瘤的快速发展，外显率达 100%，宿主生存期短。肿瘤表现出 PI3K/Akt 和 Lkb1/Ampk 信号传导失调以及 mTOR 信号传导过度激活。使用双重 PI3K/mTOR 抑制剂 BEZ235 治疗可延长肿瘤发病前的时间并延长总生存期。 PI3K 抑制剂 GDC-0941 作为单一药物使用，降低了 Pten/Lkb1 缺陷小鼠中原发性肿瘤植入物的生长速度，而 mTOR 抑制剂 RAD001 在触发肿瘤消退方面出人意料地与 BEZ235 一样有效。与此同时，我们还发现 PTEN/LKB1 缺陷的人子宫内膜癌细胞中 LKB1 的异位表达增加了它们对 PI3K 抑制的敏感性。总之，我们的结果表明，PTEN/Lkb1 缺陷的子宫内膜肿瘤强烈依赖于失调的 mTOR 信号传导，并且他们提供了 LKB1 状态可能调节 PTEN 缺陷肿瘤对 PI3K 或 mTOR 抑制剂的反应的证据。
Signals from the tumor suppressors PTEN and LKB1 converge on mTOR to negatively regulate its function in cancer cells. Notably, both of these suppressors are attenuated in a significant fraction of human endometrial tumors. In this study, we generated a genetic mouse model of endometrial cancer driven by concomitant loss of these suppressors to gain pathophysiological insight into this disease. Dual loss of Pten and Lkb1 in the endometrial epithelium led to rapid development of advanced endometrioid endometrial tumors with 100% penetrance and short host survival. The tumors displayed dysregulated PI3K/Akt and Lkb1/Ampk signaling with hyperactivation of mTOR signaling. Treatment with a dual PI3K/mTOR inhibitor, BEZ235, extended the time before tumor onset and prolonged overall survival. The PI3K inhibitor GDC-0941 used as a single agent reduced the growth rate of primary tumor implants in Pten/Lkb1-deficient mice, and the mTOR inhibitor RAD001 was unexpectedly as effective as BEZ235 in triggering tumor regression. In parallel, we also found that ectopic expression of LKB1 in PTEN/LKB1-deficient human endometrial cancer cells increased their sensitivity to PI3K inhibition. Together, our results demonstrated that Pten/Lkb1-deficient endometrial tumors rely strongly on deregulated mTOR signaling, and they provided evidence that LKB1 status may modulate the response of PTEN-deficient tumors to PI3K or mTOR inhibitors.