Department of Radiation Oncology The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Clin Cancer Res. 2012 Mar 15;18(6):1641-54. doi: 10.1158/1078-0432.CCR-11-2324. Epub 2012 Jan 24.
Ras/Raf/mitogen-activated protein-extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling is critical for tumor cell proliferation and survival. Selumetinib is a potent, selective, and orally available MEK1/2 inhibitor. In this study, we evaluated the therapeutic efficacy of selumetinib alone or with cediranib, an orally available potent inhibitor of all three VEGF receptor (VEGFR) tyrosine kinases, in murine orthotopic non-small cell lung carcinoma (NSCLC) models.
NCI-H441 or NCI-H460 KRAS-mutant human NSCLC cells were injected into the lungs of mice. Mice were randomly assigned to treatment with selumetinib, cediranib, paclitaxel, selumetinib plus cediranib, or control. When controls became moribund, all animals were sacrificed and assessed for lung tumor burden and locoregional metastasis. Lung tumors and adjacent normal tissues were subjected to immunohistochemical analyses.
Selumetinib inhibited lung tumor growth and, particularly at higher dose, reduced locoregional metastasis, as did cediranib. Combining selumetinib and cediranib markedly enhanced their antitumor effects, with near complete suppression of metastasis. Immunohistochemistry of tumor tissues revealed that selumetinib alone or with cediranib reduced ERK phosphorylation, angiogenesis, and tumor cell proliferation and increased apoptosis. The antiangiogenic and apoptotic effects were substantially enhanced when the agents were combined. Selumetinib also inhibited lung tumor VEGF production and VEGFR signaling.
In this study, we evaluated therapy directed against MEK combined with antiangiogenic therapy in distinct orthotopic NSCLC models. MEK inhibition resulted in potent antiangiogenic effects with decreased VEGF expression and signaling. Combining selumetinib with cediranib enhanced their antitumor and antiangiogenic effects. We conclude that combining selumetinib and cediranib represents a promising strategy for the treatment of NSCLC.
Ras/Raf/丝裂原活化蛋白-细胞外信号调节激酶（ERK）激酶（MEK）/ERK 信号通路对于肿瘤细胞的增殖和存活至关重要。Selumetinib 是一种有效的、选择性的、口服的 MEK1/2 抑制剂。在这项研究中，我们评估了 Selumetinib 单独或与 Cediranib（一种有效的、口服的、可抑制所有三种血管内皮生长因子受体（VEGFR）酪氨酸激酶的抑制剂）联合治疗在小鼠原位非小细胞肺癌（NSCLC）模型中的治疗效果。
将 NCI-H441 或 NCI-H460 KRAS 突变型人 NSCLC 细胞注射到小鼠肺部。将小鼠随机分为 Selumetinib、Cediranib、紫杉醇、Selumetinib 加 Cediranib 或对照组。当对照组濒死时，所有动物均被处死，并评估肺肿瘤负荷和局部转移情况。对肺肿瘤和相邻正常组织进行免疫组织化学分析。
Selumetinib 抑制了肺肿瘤的生长，特别是在高剂量时，还减少了局部转移，Cediranib 也有同样的作用。Selumetinib 与 Cediranib 联合使用显著增强了它们的抗肿瘤作用，几乎完全抑制了转移。肿瘤组织的免疫组织化学分析显示，Selumetinib 单独或与 Cediranib 联合使用可降低 ERK 磷酸化、血管生成、肿瘤细胞增殖，并增加细胞凋亡。当联合使用时，抗血管生成和凋亡作用得到了显著增强。Selumetinib 还抑制了肺肿瘤 VEGF 的产生和 VEGFR 信号通路。
在这项研究中，我们评估了针对 MEK 的治疗与针对不同原位 NSCLC 模型的抗血管生成治疗的联合应用。MEK 抑制导致了强烈的抗血管生成作用，降低了 VEGF 的表达和信号。Selumetinib 与 Cediranib 联合使用增强了它们的抗肿瘤和抗血管生成作用。我们得出结论，Selumetinib 与 Cediranib 的联合应用代表了治疗 NSCLC 的一种有前途的策略。
