Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer
Targeting inhibition of extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) suppresses growth and angiogenesis of gastric cancer
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使用 AZD6244 (ARRY-142886) 靶向抑制细胞外信号调节激酶激酶通路可抑制胃癌的生长和血管生成
DOI：
10.1038/srep16382
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发表时间：
2015-11-16
影响因子：
4.6
通讯作者：
Tang, Cheng-Wei
中科院分区：
文献类型：
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作者：
Gao, Jin-Hang;Wang, Chun-Hui;Tang, Cheng-Wei
AZD 6244（ARRY-142886）是一种高选择性的MAPK-ERK激酶抑制剂，在许多肿瘤中显示出优异的临床疗效。然而，AZD 6244对胃癌的抗肿瘤和抗血管生成功效尚未得到很好的表征。在这项研究中，p-ERK高表达与晚期TNM分期、淋巴管浸润增加和生存率低相关。由于NRAS、KRAS和BRAF突变缺失，SGC 7901和BGC 823胃癌细胞在体外对AZD 6244相对耐药。这种耐药不是由于ERK磷酸化抑制不足所致。然而，通过阻断血管生成，在SGC 7901异种移植物中肿瘤生长被显著抑制。AZD 6244处理后，HUVEC细胞中的管形成和迁移受到抑制，进一步支持了这一结果。此外，AZD 6244的抗血管生成作用可能主要归因于其通过p-ERK - c-Fos - HIF-1 α整合信号通路对VEGF的调节。结论：p-ERK高表达与肿瘤的TNM分期、淋巴管浸润和生存率相关。AZD 6244靶向抑制p-ERK，通过阻断血管生成抑制胃癌异种移植物，无全身毒性。AZD 6244的抗血管生成作用可能是通过调节p-ERK - c-Fos - HIF-1 α- VEGF整合信号通路实现的。
AZD6244 (ARRY-142886), a highly selective MAPK-ERK kinase inhibitor, has shown excellent clinical efficacy in many tumors. However, the anti-tumor and anti-angiogenesis efficacy of AZD6244 on gastric cancer has not been well characterized. In this study, high p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. For absence of NRAS, KRAS and BRAF mutation, SGC7901 and BGC823 gastric cancer cells were relative resistance to AZD6244 in vitro. And such resistance was not attributed to the insufficient inhibition of ERK phosphorylation. However, tumor growth was significantly suppressed in SGC7901 xenografts by blockage of angiogenesis. This result was further supported by suppression of tube formation and migration in HUVEC cells after treatment with AZD6244. Moreover, the anti-angiogenesis effect of AZD6244 may predominantly attribute to its modulation on VEGF through p-ERK - c-Fos - HIF-1 alpha integrated signal pathways. In conclusions, High p-ERK expression was associated with advanced TNM stage, increased lymphovascular invasion and poor survival. Targeting inhibition of p-ERK by AZD6244 suppress gastric cancer xenografts by blockage of angiogenesis without systemic toxicity. The anti-angiogenesis effect afford by AZD6244 may attribute to its modulation on p-ERK - c-Fos - HIF-1 alpha - VEGF integrated signal pathways.