The specific mechanisms how
lung cancer cells harboring
epidermal growth factor receptor (EGFR) activating mutations can survive treatment with EGFR-
tyrosine kinase inhibitors (TKIs) until they eventually acquire treatment-resistance genetic mutations are unclear. The phenotypic diversity of
cancer cells caused by genetic or epigenetic alterations (intratumor heterogeneity) confers treatment failure and may foster
tumor evolution through Darwinian selection. Recently, we found DDX3X as the
protein that was preferentially expressed in murine
melanoma with cancer stem cell (CSC)-like phenotypes by
proteome analysis. In this study, we transfected PC9, human
lung cancer cells harboring EGFR exon19 deletion, with
cDNA encoding DDX3X and found that DDX3X, an
ATP-dependent
RNA helicase, induced CSC-like phenotypes and the epithelial-mesenchymal transition (EMT) accompanied with loss of sensitivity to EGFR-TKI. DDX3X expression was associated with upregulation of Sox2 and increase of
cancer cells exhibiting CSC-like phenotypes, such as anchorage-independent proliferation, strong expression of CD44, and
aldehyde dehydrogenase (ALDH). The EMT with switching from
E-cadherin to
N-cadherin was also facilitated by DDX3X. Either
ligand-independent or
ligand-induced EGFR phosphorylation was inhibited in
lung cancer cells that strongly expressed DDX3X. Lack of EGFR signal addiction resulted in resistance to EGFR-TKI. Moreover, we found a small nonadherent subpopulation that strongly expressed DDX3X accompanied by the same stem cell-like properties and the EMT in parental PC9 cells. The unique subpopulation lacked EGFR signaling and was highly resistant to EGFR-TKI. In conclusion, our data indicate that DDX3X may play a critical role for inducing phenotypic diversity, and that treatment targeting DDX3X may overcome primary resistance to EGFR-TKI resulting from intratumor heterogeneity.