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 p21^Cip1 and p27^Kip1. 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 p21^Cip1 and p27^Kip1. 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.