Effects of combined inhibition of MEK and mTOR on downstream signaling and tumor growth in pancreatic cancer xenograft models
Effects of combined inhibition of MEK and mTOR on downstream signaling and tumor growth in pancreatic cancer xenograft models
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DOI：
10.4161/cbt.8.20.9430
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发表时间：
2009-10-15
影响因子：
3.6
通讯作者：
Hedley, David W.
中科院分区：
文献类型：
--
作者：
Chang, Qing;Chen, Eric;Hedley, David W.
ERK 和 mTOR 通路显示出协调生长激活和蛋白质翻译调节的多重互连。尽管针对这些途径的药物作为单一药物的抗癌作用似乎有限，但我们假设这些药物的单一治疗抗癌功效可以通过它们的组合来增强。使用 BxPC-3 和 MIA PaCa-2 胰腺癌模型对 MEK 抑制剂 AZD6244 (ARRY-142886) 和 mTOR 抑制剂雷帕霉素作为单药和联合用药进行了体内测试。在这两种模型中，联合治疗几乎完全抑制 S6 核糖体蛋白，但单一药物仅部分抑制。此外，与单一药物相比，通过 caspase 3 裂解和使用溴脱氧尿苷掺入测量的生长抑制表明，联合药物治疗 48 小时产生了更大的细胞凋亡。肿瘤 VEGF ELISA 测定和 CD31 分析显示，AZD6244 但雷帕霉素没有表现出显着的抗血管生成作用。血浆和肿瘤药代动力学分析表明，AZD6244 在肿瘤组织中积聚的浓度可在体外产生靶点抑制和细胞周期停滞。在长期给药实验中，药物组合具有良好的耐受性，并且与单一药物相比显示出更大的生长抑制作用。这些结果与 ERK 和 mTOR 信号在多个水平上相互作用以调节体内肿瘤生长的假设一致，并支持在胰腺癌患者中测试 MEK 加 mTOR 抑制剂组合。
The ERK and mTOR pathways show multiple interconnections that coordinate growth activation and the regulation of protein translation. Although drugs that target these pathways appear to have limited anti-cancer effects as single agents, we hypothesized that the monotherapy anticancer efficacy of these agents could be enhanced by their combination. The MEK inhibitor AZD6244 (ARRY-142886) and the mTOR inhibitor rapamycin were tested as single agents and in combination, using BxPC-3 and MIA PaCa-2 pancreatic cancer models in vivo. In both models, S6 ribosomal protein was almost completely inhibited with combined treatment, but only partially inhibited with the single agents. In addition, 48 h treatment with the drug combination produced greater apoptosis, revealed by caspase 3 cleavage, and growth inhibition measured using bromodeoxyuridine incorporation, compared to the single agents. AZD6244 but not rapamycin exhibited a significant anti-angiogenic effect, as shown by tumor VEGF ELISA assay and CD31 analysis. Plasma and tumor pharmacokinetic analyses indicated that AZD6244 accumulates in tumor tissue at concentrations that produce target inhibition and cell cycle arrest in vitro. In chronic dosing experiments, the drug combination was well tolerated, and showed greater growth inhibition compared to the single agents. These results are consistent with the hypothesis that ERK and mTOR signaling interact at multiple levels to regulate tumor growth in vivo, and support the testing of MEK plus mTOR inhibitor combinations in pancreatic cancer patients.