Abstract: Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are remarkably effective against non-small-cell lung cancer (NSCLC) with EGFR-activating mutations, lung cancer cells acquire resistance to EGFR-TKIs without exception. Several mechanisms of EGFR-TKI resistance have been reported, but there are many aspects that remain to be clarified. We previously identified DDX3X as an immunogenic protein preferentially expressed in murine melanoma with a cancer stem cell (CSC)-like phenotype. DDX3X induced epithelial-mesenchymal transition and reduced the sensitivity to EGFR-TKIs in PC9 cells, human lung cancer cells harboring EGFR exon 19 deletion. We also reported that there was a small nonadherent subpopulation of parental PC9 cells that highly expressed DDX3X and had CSC properties. In this study, we found that VEGFR2 was upregulated in lung cancer cells that strongly expressed DDX3X and that these cells were addicted to VEGFR signaling. The blockade of both EGFR and VEGFR signaling reduced the phosphorylation of downstream signals in the cells with DDX3X that acquired EGFR-TKI resistance. The addition of VEGFR-TKIs or anti-VEGF antibodies to EGFR-TKIs significantly inhibited the progression of EGFR-mutated NSCLC in a xenograft mouse model. These data suggest that the blockade of VEGFR signaling enhances the antitumor effects of EGFR-TKIs by eradicating cancer stem cells, which mediate resistance to EGFR-TKIs.

Journal Link: 10.21203/rs.3.rs-1073662/v1 Journal Link: Publisher Website Journal Link: Download PDF Journal Link: Google Scholar