Dual inhibition of PI3K and mTOR signaling pathways decreases human pancreatic neuroendocrine tumor metastatic progression.
Dual inhibition of PI3K and mTOR signaling pathways decreases human pancreatic neuroendocrine tumor metastatic progression.
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DOI：
10.1097/mpa.0b013e3182a44ab4
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发表时间：
2014-01
期刊：
影响因子：
2.9
通讯作者：
Chao C
中科院分区：
文献类型：
--
作者：
Djukom C;Porro LJ;Mrazek A;Townsend CM Jr;Hellmich MR;Chao C
晚期胰腺神经内分泌肿瘤（PNET）患者的治疗选择有限。RAD001是哺乳动物雷帕霉素靶蛋白（mTOR）通路的一种抑制剂，已被证明可提高无进展生存期，但不能提高总生存期，这表明需要确定其他治疗靶点。RAD001对mTORC1的抑制可能会诱导上游AKT的上调。我们假设同时抑制AKT和mTOR将克服RAD001单独使用时活性有限的问题。
BON细胞系已被用作研究PNET细胞生物学的模型。采用mTOR抑制剂RAD001（50 nM）、MEK抑制剂PD0325901（50 nM）、PI3K抑制剂LY294002（25 μM）或溶媒对照进行蛋白质印迹和细胞生长测定。在脾内注射BON细胞一周后，裸鼠每日接受RAD001（灌胃）、LY29400（皮下注射）治疗6周。
联合使用LY29400和RAD001对细胞增殖的抑制作用最强。同样，与溶媒组相比，同时使用LY29400（100 mg/kg/周，皮下注射）和RAD001（2.5 mg/kg/天）治疗组的肝转移瘤体积最小（p = 0.04）。
与溶媒或单一药物相比，LY29400和RAD001联合使用可降低体外细胞生长和体内肝转移的进展。
Patients with advanced pancreatic neuroendocrine tumors (PNET) have limited therapeutic options. RAD001, an inhibitor of the mammalian target of rapamycin (mTOR) pathway, has been shown to increase progression-free survival, but not overall survival, indicating a need to identify additional therapeutic targets. Inhibition of mTORC1 by RAD001 may induce upstream AKT upregulation. We hypothesized that dual inhibition of AKT along with mTOR will overcome the limited activity of RAD001 alone. The BON cell line has been used as a model to study PNET cell biology. Western blots and cell growth assays were performed with mTOR inhibitor RAD001 (50 nM), MEK inhibitor PD0325901 (50 nM), PI3K inhibitor LY294002 (25 μM) or vehicle control. Nude mice were treated daily for 6 weeks with RAD001 (oral gavage), LY29400 (SQ) one week after intrasplenic injection of BON cells. Cellular proliferation was most attenuated with the combination therapy LY29400 and RAD001. Similarly, the volume of liver metastasis was lowest in the group treated with both LY29400 (100 mg/kg/week, SQ) and RAD001 (2.5 mg/kg/d) compared to vehicle (p=0.04). The combination LY29400 and RAD001 decreased the cell growth in vitro and progression of liver metastasis in vivo compared vehicle or to single drug.