Preclinical activity of the rational combination of selumetinib (AZD6244) in combination with vorinostat in KRAS-mutant colorectal cancer models.
Preclinical activity of the rational combination of selumetinib (AZD6244) in combination with vorinostat in KRAS-mutant colorectal cancer models.
复制标题
DOI：
10.1158/1078-0432.ccr-11-1507
复制
发表时间：
2012-02-15
期刊：
影响因子：
--
通讯作者：
Eckhardt SG
中科院分区：
文献类型：
--
作者：
Morelli MP;Tentler JJ;Kulikowski GN;Tan AC;Bradshaw-Pierce EL;Pitts TM;Brown AM;Nallapareddy S;Arcaroli JJ;Serkova NJ;Hidalgo M;Ciardiello F;Eckhardt SG
尽管有多种有效的联合治疗方案可用于晚期结直肠癌（CRC），但其5年生存率仍低于10%，这为开发新的治疗方法提供了支持。在这项研究中，我们通过测试MEK抑制剂selumetinib和vorinostat（一种组蛋白脱乙酰酶（HDAC）抑制剂）的组合，重点关注对KRAS突变CRC的合理组合的临床前评估。CRC细胞系的转录谱分析和基因集富集分析（基线和治疗后）提供了组合的基本原理。在体外和体内研究了司美替尼和伏立诺他对KRAS突变体SW 620和SW 480 CRC细胞系的活性。使用单层和三维培养、流式细胞术、细胞凋亡和细胞迁移评估该组合对肿瘤表型的影响。在体内，肿瘤生长抑制，18 F-氟-脱氧葡萄糖正电子发射断层扫描（FDG-PET）和质子核磁共振进行了评估的生长抑制和代谢反应，分别在CRC异种移植。在体外，用司美替尼和伏立诺他处理导致两种CRC细胞系中的增殖和球体形成的协同抑制。这种抑制作用与细胞凋亡增加、G1期细胞周期阻滞以及细胞迁移和VEGF-A分泌减少有关。在体内，该组合导致累加的肿瘤生长抑制。对司美替尼和伏立诺他的代谢反应包括对膜磷脂的显著抑制;在任何治疗组中均未观察到葡萄糖摄取或代谢的显著变化。这些数据表明，丝裂原活化蛋白激酶/细胞外信号调节激酶抑制剂司美替尼与HDAC抑制剂伏立诺他的合理组合在体外产生针对KRAS突变CRC细胞系的协同抗增殖活性。在体内，该组合显示出与磷脂周转代谢变化相关的累加效应，但对FDG-PET无影响，表明前者是组合效应的更敏感终点。
Despite the availability of several active combination regimens for advanced colorectal cancer (CRC), the 5-year survival rate remains poor at less than 10%,supporting the development of novel therapeutic approaches. In this study, we focused on the preclinical assessment of a rationally based combination against KRAS-mutated CRC by testing the combination of the MEK inhibitor, selumetinib, and vorinostat, a histone deacetylase (HDAC) inhibitor. Transcriptional profiling and gene set enrichment analysis (baseline and post-treatment) of CRC cell lines provided the rationale for the combination. The activity of selumetinib and vorinostat against the KRAS-mutant SW620 and SW480 CRC cell lines was studied in vitro and in vivo. The effects of this combination on tumor phenotype were assessed using monolayer and 3-dimensional cultures, flow cytometry, apoptosis, and cell migration. In vivo, tumor growth inhibition, 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET), and proton nuclear magnetic resonance were carried out to evaluate the growth inhibitory and metabolic responses, respectively, in CRC xenografts. In vitro, treatment with selumetinib and vorinostat resulted in a synergistic inhibition of proliferation and spheroid formation in both CRC cell lines. This inhibition was associated with an increase in apoptosis, cell-cycle arrest in G1, and reduced cellular migration and VEGF-A secretion. In vivo, the combination resulted in additive tumor growth inhibition. The metabolic response to selumetinib and vorinostat consisted of significant inhibition of membrane phospholipids; no significant changes in glucose uptake or metabolism were observed in any of the treatment groups. These data indicate that the rationally based combination of the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, selumetinib, with the HDAC inhibitor vorinostat results in synergistic antiproliferative activity against KRAS-mutant CRC cell lines in vitro. In vivo, the combination showed additive effects that were associated with metabolic changes in phospholipid turnover, but not on FDG-PET, indicating that the former is a more sensitive endpoint of the combination effects.