Division of Medical Oncology, Department of Anesthesiology and Radiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA.
Clin Cancer Res. 2012 Feb 15;18(4):1051-62. doi: 10.1158/1078-0432.CCR-11-1507. Epub 2011 Dec 15.
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 posttreatment) 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, (18)F-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 G(1), 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.
尽管有几种针对晚期结直肠癌（CRC）的活性联合治疗方案，但 5 年生存率仍较低，不足 10%，这支持了新型治疗方法的开发。在这项研究中，我们通过测试 MEK 抑制剂 selumetinib 与组蛋白去乙酰化酶（HDAC）抑制剂 vorinostat 的联合用药，对针对 KRAS 突变型 CRC 的合理联合治疗进行了临床前评估。
对 CRC 细胞系进行转录谱分析和基因集富集分析（基线和治疗后），为联合用药提供了依据。在体外和体内研究了 selumetinib 和 vorinostat 对 KRAS 突变型 SW620 和 SW480 CRC 细胞系的活性。使用单层和 3 维培养、流式细胞术、细胞凋亡和细胞迁移评估该联合用药对肿瘤表型的影响。在体内，通过进行肿瘤生长抑制、（18）F-氟脱氧葡萄糖正电子发射断层扫描（FDG-PET）和质子磁共振波谱，分别评估 CRC 异种移植的生长抑制和代谢反应。
在体外，selumetinib 和 vorinostat 的联合治疗导致两种 CRC 细胞系的增殖和球体形成均协同抑制。这种抑制与凋亡增加、G1 期细胞周期停滞以及细胞迁移和 VEGF-A 分泌减少有关。在体内，联合治疗导致肿瘤生长抑制的相加作用。selumetinib 和 vorinostat 的代谢反应包括膜磷酯的显著抑制；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 selumetinib 与 HDAC 抑制剂 vorinostat 的合理联合应用可在体外对 KRAS 突变型 CRC 细胞系产生协同的抗增殖活性。在体内，联合治疗表现出相加作用，与磷脂周转率的代谢变化相关，但与 FDG-PET 无关，这表明前者是联合治疗效果的更敏感终点。
