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Updated: Jan 22, 2026

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

Published on: September 19, 2018

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CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC

Jeffrey H Becker1,2,3, Yandi Gao3, Margaret Soucheray3

  • 1Department of Surgery, Division of Cardiothoracic Surgery, University of Illinois at Chicago, Chicago, Illinois.

Cancer Research
|July 6, 2019
PubMed

Insights

Chemokine receptor CXCR7 reactivates ERK signaling, driving acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in non-small cell lung cancer. Inhibiting CXCR7 may prevent or delay this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • EGFR tyrosine kinase inhibitors (TKI) are effective against EGFR-mutant non-small cell lung cancer (NSCLC).
  • Acquired resistance to EGFR-TKI therapy can develop, often involving reactivation of the MAPK-ERK pathway.
  • Understanding resistance mechanisms is crucial for improving NSCLC treatment outcomes.

Purpose of the Study:

  • To investigate the role of CXCR7 in acquired resistance to EGFR-TKI in NSCLC.
  • To elucidate the signaling pathway through which CXCR7 contributes to resistance.
  • To assess the therapeutic potential of targeting CXCR7 in EGFR-mutant NSCLC.

Main Methods:

  • Utilized in vitro models of acquired EGFR TKI resistance with a mesenchymal phenotype.
  • Investigated the role of CXCR7 in activating the MAPK-ERK pathway via β-arrestin.
  • Assessed the effects of CXCR7 depletion on EGFR TKI resistance and cell phenotype.
  • Analyzed CXCR7 expression in patient samples of NSCLC with acquired resistance.

Main Results:

  • CXCR7 activates the MAPK-ERK pathway via β-arrestin in EGFR TKI-resistant cells.
  • Depletion of CXCR7 inhibited the MAPK pathway, attenuated EGFR TKI resistance, and induced mesenchymal-to-epithelial transition.
  • CXCR7 overexpression was essential for ERK1/2 reactivation in EGFR TKI-resistant persister cells.
  • Increased CXCR7 expression was observed in NSCLC patients who progressed on EGFR inhibitors.

Conclusions:

  • CXCR7 plays a significant role in acquired resistance to EGFR-TKI in EGFR-mutant NSCLC.
  • CXCR7-mediated ERK reactivation is a key mechanism driving resistance.
  • Targeting CXCR7 may represent a viable strategy to overcome or prevent acquired EGFR TKI resistance in NSCLC.

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