AZD6244 (ARRY-142886) Enhances the Antitumor Activity of Rapamycin in Mouse Models of Human Hepatocellular Carcinoma
AZD6244 (ARRY-142886) Enhances the Antitumor Activity of Rapamycin in Mouse Models of Human Hepatocellular Carcinoma
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DOI：
10.1002/cncr.24863
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发表时间：
2010-03-01
期刊：
影响因子：
6.2
通讯作者：
Huynh, Hung
中科院分区：
文献类型：
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作者：
Huynh, Hung
背景技术背景：蛋白激酶B（AKT）/哺乳动物雷帕霉素靶蛋白（mTOR）和丝裂原活化蛋白激酶/细胞外调节激酶激酶/细胞外调节激酶（MEK/ERK）信号通路在肝细胞癌（HCC）的生长和血管生成中起重要作用，提示抑制这些通路可能具有治疗潜力。方法：我们用1）mTOR抑制剂雷帕霉素（RAPA）; 2）MEK抑制剂AZD 6244（ARRY-142886）;和3）AZD 6244 + RAPA（AZD 6244/RAPA）治疗患者来源的HCC异种移植物。Western印迹法用于确定与血管生成、mTOR通路和MEK信号传导相关的生物标志物的药效学变化。通过免疫组化分析细胞凋亡、微血管密度和细胞增殖。研究结果：我们在此报告，AZD 6244对MEK/ERK通路的药理学抑制增强了mTOR抑制剂RAPA在原位和异位HCC模型中的抗肿瘤和抗血管生成活性。这种抑制导致细胞凋亡增加，血管生成和细胞增殖减少，细胞周期调节因子阳性表达减少，促凋亡蛋白Bim增加。结论：我们的研究结果表明，AZD 6244/RAPA组合在人HCC临床前模型中具有抗肿瘤和抗血管生成作用。考虑到对HCC有效治疗的迫切需求，对AZD 6244/RAPA联合治疗进行临床评价似乎是必要的。Cancer 2010;116：1315-25. (C)2010美国癌症协会
BACKGROUND: The protein kinase B (AKT)/mammalian target of rapamycin (AKT/mTOR) and mitogen activated protein kinase/extracellular regulated kinase kinase/extracellular regulated kinase (MEK/ERK) signaling pathways have been shown to play an important role in hepatocellular carcinoma (HCC) growth and angiogenesis, suggesting that inhibition of these pathways may have therapeutic potential. METHODS: We treated patient-derived HCC xenografts with 1) mTOR inhibitor rapamycin (RAPA); 2) MEK inhibitor AZD6244 (ARRY-142886); and 3) AZD6244 plus RAPA (AZD6244/RAPA). Western blotting was used to determine pharmacodynamic changes in biomarkers relevant to angiogenesis, mTOR pathway, and MEK signaling. Apoptosis, microvessel density, and cell proliferation were analyzed by immunohistochemistry. RESULTS: We report here that pharmacological inhibition of the MEK/ERK pathway by AZD6244 enhanced the antitumor and antiangiogenic activities of mTOR inhibitor RAPA in both orthotopic and ectopic models of HCC. Such inhibition led to increased apoptosis, decreased angiogenesis and cell proliferation, reduced expression of positive cell cycle regulators, and increase in proapoptotic protein Bim. CONCLUSIONS: Our findings indicate that the AZD6244/RAPA combination had antitumor and antiangiogenic effects in preclinical models of human HCC. Given the urgent need for effective therapies in HCC, clinical evaluating AZD6244/RAPA combination seems warranted. Cancer 2010;116:1315-25. (C) 2010 American Cancer Society.