Non–small cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in EGFR, KRAS, and various ALK fusions. However, despite effective treatments for EGFR and ALK, promising therapeutics have not been developed for patients with KRAS mutations. It has been reported that one way the RAS–ERK pathway contributes to tumorigenesis is by affecting stability and localization of FOXO3a protein, an important regulator of cell death and the cell cycle. This is through regulation of apoptotic proteins BIM and FASL and cell-cycle regulators p21Cip1 and p27Kip1. We now show that an HDAC inhibitor affects the expression and localization of FOXO proteins and wanted to determine whether the combination of a MEK inhibitor with an HDAC inhibitor would increase the sensitivity of NSCLC with KRAS mutation. Combined treatment with a MEK inhibitor and an HDAC inhibitor showed synergistic effects on cell metabolic activity of RAS-mutated lung cancer cells through activation of FOXOs, with a subsequent increase in BIM and cell-cycle inhibitors. Moreover, in a mouse xenograft model, the combination of belinostat and trametinib significantly decreases tumor formation through FOXOs by increasing BIM and the cell-cycle inhibitors p21Cip1 and p27Kip1. These results demonstrate that control of FOXOs localization and expression is critical in RAS-driven lung cancer cells, suggesting that the dual molecular-targeted therapy for MEK and HDACs may be promising as novel therapeutic strategy in NSCLC with specific populations of RAS mutations. Mol Cancer Ther; 17(1); 17–25. ©2017 AACR.

中文翻译：

---

组蛋白去乙酰化酶抑制增强了 MEK 抑制剂在携带 RAS 突变的肺癌细胞中的抗肿瘤活性

非小细胞肺癌 (NSCLC) 可以通过基于驱动肿瘤发生的基因组改变的精确分子亚群来识别，包括 EGFR、KRAS 和各种 ALK 融合的突变。然而，尽管对 EGFR 和 ALK 进行了有效的治疗，但尚未为 KRAS 突变患者开发出有前景的治疗方法。据报道，RAS-ERK 通路促进肿瘤发生的一种方式是影响 FOXO3a 蛋白的稳定性和定位，FOXO3a 蛋白是细胞死亡和细胞周期的重要调节剂。这是通过调节凋亡蛋白 BIM 和 FASL 以及细胞周期调节因子 p21Cip1 和 p27Kip1 实现的。我们现在表明 HDAC 抑制剂影响 FOXO 蛋白的表达和定位，并想确定 MEK 抑制剂与 HDAC 抑制剂的组合是否会增加具有 KRAS 突变的 NSCLC 的敏感性。MEK 抑制剂和 HDAC 抑制剂的联合治疗通过激活 FOXO 对 RAS 突变的肺癌细胞的细胞代谢活性显示出协同作用，随后 BIM 和细胞周期抑制剂的增加。此外，在小鼠异种移植模型中，belinostat 和曲美替尼的组合通过增加 BIM 和细胞周期抑制剂 p21Cip1 和 p27Kip1，显着减少了 FOXO 的肿瘤形成。这些结果表明 FOXOs 定位和表达的控制在 RAS 驱动的肺癌细胞中至关重要，这表明 MEK 和 HDAC 的双分子靶向治疗可能有望成为具有特定 RAS 突变群体的 NSCLC 的新型治疗策略。摩尔癌症治疗; 17(1); 17-25。©2017 AACR。