The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib provide significant clinical benefit for non-small cell lung cancer (NSCLC) patients whose tumors bear EGFR mutations/amplifications. However, anti-EGFR therapy is largely ineffective in NSCLC with activating KRAS mutations. In this study, we investigated the treatment efficacy of erlotinib and gefitinib in combination with the histone deacetylase inhibitors (HDACi) vorinostat and sodium butyrate in the KRAS-mutated NSCLC cell line A549. For comparison, we tested the combination of HDACi with the dual tyrosine kinase inhibitor lapatinib. A549 cells proved to be resistant to erlotinib and gefitinib, but could be sensitized by cotreatment with HDACi, as assessed by flow cytometric analyses of cell death and mitochondrial depolarization. In contrast, A549 cells were a priori responsive to lapatinib treatment, but responsiveness to lapatinib could not be enhanced by HDACi cotreatment. These divergent effects of the different combination regimens may be explained by dissimilar types of cell death induced by the treatments: The use of the pan-caspase inhibitor z-VAD-fmk in the cell death and mitochondrial depolarization assays as well as fluorescence microscopy analyses indicated that erlotinib or gefitinib combined with HDACi elicited apoptosis, whereas lapatinib treatment induced a non-apoptotic type of cell death. Our study suggests that both HDACi/EGFR inhibitor-combination treatment and lapatinib-single treatment may be effective options for the therapy of NSCLC with KRAS mutations.

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