Colorectal carcinomas harbor well-defined genetic abnormalities, including aberrant activation of Wnt/β-catenin and MAPK pathways, often simultaneously. Although the MAPK pathway can be targeted using potent small-molecule drugs, including BRAF and MEK inhibitors, β-catenin inhibition has been historically challenging. RNAi approaches have advanced to the stage of clinical viability and are especially well suited for transcriptional modulators, such as β-catenin. In this study, we report therapeutic effects of combined targeting of these pathways with pharmacologic agents. Using a recently described tumor-selective nanoparticle containing a β-catenin–targeting RNAi trigger, in combination with the FDA-approved MEK inhibitor (MEKi) trametinib, we demonstrate synergistic tumor growth inhibition in in vivo models of colorectal cancer, melanoma, and hepatocellular carcinoma. At dose levels that were insufficient to significantly impact tumor growth as monotherapies, combination regimens resulted in synergistic efficacy and complete tumor growth inhibition. Importantly, dual MEKi/RNAi therapy dramatically improved survival of mice bearing colorectal cancer liver metastases. In addition, pharmacologic silencing of β-catenin mRNA was effective against tumors that are inherently resistant or that acquire drug-induced resistance to trametinib. These results provide a strong rationale for clinical evaluation of this dual-targeting approach for cancers harboring Wnt/β-catenin and MAPK pathway mutations. Mol Cancer Ther; 17(2); 544–53. ©2017 AACR.

中文翻译：

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β-Catenin mRNA 沉默和 MEK 抑制在临床前肿瘤模型中显示出协同功效


结直肠癌具有明确的遗传异常，包括 Wnt/β-catenin 和 MAPK 通路的异常激活（通常同时发生）。尽管可以使用有效的小分子药物（包括 BRAF 和 MEK 抑制剂）来靶向 MAPK 通路，但 β-连环蛋白抑制在历史上一直具有挑战性。 RNAi 方法已进入临床可行性阶段，特别适合转录调节剂，例如 β-连环蛋白。在这项研究中，我们报告了与药物制剂联合靶向这些途径的治疗效果。使用最近描述的含有 β-连环蛋白靶向 RNAi 触发器的肿瘤选择性纳米颗粒，与 FDA 批准的 MEK 抑制剂 (MEKi) 曲美替尼 (trametinib) 相结合，我们在结直肠癌、黑色素瘤和肝细胞的体内模型中证明了协同肿瘤生长抑制作用癌。在单一疗法不足以显着影响肿瘤生长的剂量水平下，联合治疗方案产生协同功效并完全抑制肿瘤生长。重要的是，MEKi/RNAi 双重疗法显着提高了结直肠癌肝转移小鼠的存活率。此外，β-连环蛋白 mRNA 的药理学沉默可有效对抗对曲美替尼具有固有耐药性或获得药物诱导耐药性的肿瘤。这些结果为这种针对携带 Wnt/β-连环蛋白和 MAPK 通路突变的癌症的双靶向方法的临床评估提供了强有力的依据。摩尔癌症治疗； 17(2)； 544–53。 ©2017 AACR。