EGFR-Tyrosine Kinase Inhibitors Induced Activation of the Autocrine CXCL10/CXCR3 Pathway through Crosstalk between the Tumor and the Microenvironment in EGFR-Mutant Lung Cancer

SIMPLE SUMMARY: Recent studies have sought to evaluate early oncogenic signaling in EGFR-mutant lung cancers under EGFR-TKI treatment, but few studies have evaluated the effect of the tumor microenvironment on persistent tumor cells under EGFR-TKI treatment. Our study demonstrates that CXCL10, a representative inflamed immune-response cytokine, activates CXCR3 in tumor cells to induce the phosphorylation of Src and the NF-κB subunit, p65, and the expression of HIF1-α in persistent EGFR-mutant tumor cells during EGFR-TKI treatment. We further reveal that the CXCL10/CXCR3 signaling of tumor cells is augmented via an autocrine pathway. Our study reveals that the EGFR-TKI-treatment-related oncogenic pathway changes contributing to EGFR-TKI resistance in EGFR-mutant NSCLC are paradoxically attributed to the targeting of tumor cells by an activated immune system. ABSTRACT: CXCL10 is a cytokine that is elevated during EGFR-TKI treatment in the tumor microenvironment of lung cancer. Here, we report an original study that the impact of the CXCL10/CXCR3 pathway on EGFR-TKI resistance in EGFR-mutant lung cancer through a cytokine array analysis during in vitro coculture with tumor cells and activated PBMCs treated with EGFR-TKI, as well as the serial analysis of CXCL10 in EGFR-mutant lung cancer transgenic mice during EGFR-TKI treatment. In EGFR-mutant tumor cells cocultured with activated PBMCs, EGFR-TKI treatment increased CXCL10 in the supernatant; this activated CXCR3 in the tumor cells to induce the phosphorylation of Src and the NF-κB subunit, p65, and the expression of HIF-1α. CXCL10 siRNA treatment of EGFR-mutant tumor cells also decreased CXCL10 in the supernatant from coculturing with activated PBMCs, suggesting that the effects of CXCL10 occur via autocrine and paracrine pathways. Importantly, elevated CXCL10/CXCR3 signaling was recapitulated in a transgenic lung cancer mouse model. Our results show that increased CXCL10 levels during early EGFR-TKI treatment stimulate oncogenic signaling of persistent tumor cells to contribute to EGFR-TKI resistance via autocrine and paracrine pathways.