EGFR-Tyrosine Kinase Inhibitors Induced Activation of the Autocrine CXCL10/CXCR3 Pathway through Crosstalk between the Tumor and the Microenvironment in EGFR-Mutant Lung Canceropen access
- Authors
- Hong, Sook-hee; Kang, Nahyeon; Kim, Okran; Hong, Soon Auck; Park, Juyeon; Kim, Joori; Lee, Myung-Ah; Kang, Jinhyoung
- Issue Date
- Jan-2023
- Publisher
- MDPI
- Keywords
- EGFR mutation; lung cancer; EGFR-TKI; tyrosine kinase inhibitor; CXCL10; CXCR3; NF-kappa B; HIF-1 alpha
- Citation
- CANCERS, v.15, no.1
- Journal Title
- CANCERS
- Volume
- 15
- Number
- 1
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/70495
- DOI
- 10.3390/cancers15010124
- ISSN
- 2072-6694
2072-6694
- Abstract
- CXCL10 is a cytokine that is elevated during EGFR-TKI treatment in the tumor microenvi-ronment 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 phospho-rylation of Src and the NF-KB subunit, p65, and the expression of HIF-1a. CXCL10 siRNA treatment of EGFR-mutant tumor cells also decreased CXCL10 in the supernatant from coculturing with acti-vated 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.
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