mTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer.
mTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer.
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DOI：
10.1158/0008-5472.can-16-0810
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发表时间：
2016-12-01
期刊：
影响因子：
11.2
通讯作者：
Morton JP
中科院分区：
文献类型：
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作者：
Driscoll DR;Karim SA;Sano M;Gay DM;Jacob W;Yu J;Mizukami Y;Gopinathan A;Jodrell DI;Evans TR;Bardeesy N;Hall MN;Quattrochi BJ;Klimstra DS;Barry ST;Sansom OJ;Lewis BC;Morton JP
mTOR 信号传导控制着多种关键的细胞功能，并且在包括胰腺癌在内的许多癌症中不受管制。迄今为止，大多数努力都集中在抑制 mTORC1 复合物上。然而，mTORC1 抑制剂治疗胰腺癌的临床试验失败了，引发了人们对这种治疗方法的质疑。我们采用遗传方法删除 mTORC2 专性亚基 Rictor，并确定了肿瘤发生需要 mTORC2 信号传导的关键时刻。 Rictor 缺失导致肿瘤发生大大延迟。虽然之前的研究表明大多数胰腺肿瘤对雷帕霉素不敏感，但使用双重 mTORC1/2 抑制剂治疗可强烈抑制肿瘤发生。在晚期荷瘤小鼠中，mTORC1/2 和 PI3K 联合抑制可显着提高生存率。因此，靶向 mTOR 可能是胰腺癌的潜在治疗策略。
mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor deletion resulted in profoundly delayed tumorigenesis. Whereas previous studies showed most pancreatic tumors were insensitive to rapamycin, treatment with a dual mTORC1/2 inhibitor strongly suppressed tumorigenesis. In late-stage tumor-bearing mice, combined mTORC1/2 and PI3K inhibition significantly increased survival. Thus, targeting mTOR may be a potential therapeutic strategy in pancreatic cancer.