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

Sook Hee Hong, Nahyeon Kang, Okran Kim, Soon Auck Hong, Juyeon Park, Joori Kim, Myung Ah Lee, Jinhyoung Kang

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish
Article number124
JournalCancers
Volume15
Issue number1
DOIs
StatePublished - Jan 2023

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) funded by the 2021 Ministry of Education (2021R1F1A1062232), the Catholic Medical Center Research Foundation made in the program year of 2017, the Research Fund of Seoul St. Mary’s Hospital, The Catholic University of Korea.

Publisher Copyright:
© 2022 by the authors.

Keywords

  • CXCL10
  • CXCR3
  • EGFR mutation
  • EGFR-TKI
  • HIF-1α
  • lung cancer
  • NF-κB
  • tyrosine kinase inhibitor

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