Data from Histone Deacetylase Inhibition Enhances the Antitumor Activity of a MEK Inhibitor in Lung Cancer Cells Harboring <i>RAS</i> Mutations

Abstract

<div>Abstract<p>Non–small cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in <i>EGFR, KRAS</i>, and various <i>ALK</i> fusions. However, despite effective treatments for EGFR and ALK, promising therapeutics have not been developed for patients with <i>KRAS</i> 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 p21<sup>Cip1</sup> and p27<sup>Kip1</sup>. 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 <i>KRAS</i> mutation. Combined treatment with a MEK inhibitor and an HDAC inhibitor showed synergistic effects on cell metabolic activity of <i>RAS</i>-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 p21<sup>Cip1</sup> and p27<sup>Kip1</sup>. These results demonstrate that control of FOXOs localization and expression is critical in <i>RAS</i>-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 <i>RAS</i> mutations. <i>Mol Cancer Ther; 17(1); 17–25. ©2017 AACR</i>.</p></div>