Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma
Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma
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DOI：
10.1158/1535-7163.mct-06-0436
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发表时间：
2007-01-01
影响因子：
5.7
通讯作者：
Tran, Evelyn
中科院分区：
文献类型：
--
作者：
Huynh, Hung;Soo, Khee Chee;Tran, Evelyn
肝细胞癌（HCC）是亚洲和非洲常见的恶性肿瘤。我们以前报道过，细胞外信号调节激酶（ERK）激酶1/2（MEK 1/2）和ERK 1/2的过度表达在HCC中检测到，它们的激活是肝癌细胞增殖和存活所必需的。在本研究中，我们确定了特异性MEK 1/2抑制剂AZD 6244（ARRAY-142886）治疗HCC的疗效。用AZD 6244处理原代HCC细胞导致生长抑制，caspase-3和caspase-7的切割以及切割的聚（ADP）核糖聚合酶升高，但ERK 1/2和p90 RSK磷酸化受到抑制。研究7个HCC异种移植物的蛋白质表达谱显示，它们的生长速率与磷酸化MEK的水平呈正相关。AZD 6244，当p.o.对携带这些异种移植物的小鼠，导致肿瘤生长的剂量依赖性抑制。AZD 6244诱导的生长抑制与ERK 1/2和p90 RSK的失活、活化的caspase-3和caspase-7以及裂解的聚（ADP）核糖聚合酶的上调有关。我们的数据表明MEK-ERK通路在肝癌细胞的生长和存活中起着重要作用，并且HCC异种移植模型是筛选临床前药物的极好工具。AZD 6244靶向抑制MEK-ERK通路可能是治疗这种疾病的另一种方法。
Hepatocellular carcinoma (HCC) is a common malignancy in Asia and Africa. We previously reported that overexpression of extracellular signal-regulated kinase (ERK) kinase 1/2 (MEK1/2) and ERK1/2 was detected in HCC, and that their activation was required for liver cancer cell proliferation and survival. In the present study, we determined the efficacy of a specific MEK1/2 inhibitor AZD6244 (ARRAY-142886) in treatment of HCC. Treatment of primary HCC cells with AZD6244 led to growth inhibition, elevation of the cleavage of caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase, but inhibition of ERK1/2 and p90RSK phosphorylation. Studying the protein expression profile of seven HCC xenografts revealed that their growth rate was positively correlated with the levels of phosphorylated MEK. AZD6244, when given p.o. to mice bearing these xenografts, resulted in a dose-dependent inhibition of tumor growth. AZD6244-induced growth suppression was associated with inactivation of ERK 1/2 and p90RSK, and up-regulation of activated caspase-3 and caspase-7, and cleaved poly(ADP)ribose polymerase. Our data suggest that the MEK-ERK pathway plays an important role in the growth and survival of liver cancer cells and that the HCC xenograft models are excellent tools for screening preclinical drugs. Targeted inhibition of the MEK-ERK pathway with AZD6244 may represent an alternative approach for the treatment of this disease.