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Updated: Oct 26, 2025

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Trop2 binding IGF2R induces gefitinib resistance in NSCLC by remodeling the tumor microenvironment

Xia Sun1, Lizhou Jia2,3, Tengqi Wang3

  • 1Emergency Center, Bayannur Hospital, Bayannur, Inner Mongolia, 015000, China.

Journal of Cancer
|August 2, 2021
PubMed

Insights

Trop2 promotes gefitinib resistance in non-small cell lung cancer (NSCLC) by activating the IGF2-IGF1R-Akt pathway. Targeting Trop2 and IGF1R may overcome drug resistance and reshape the tumor microenvironment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Gefitinib is effective for advanced non-small cell lung cancer (NSCLC), but drug resistance is a significant clinical issue.
  • The tumor microenvironment (TME) and its interactions with cancer cells contribute to gefitinib resistance.
  • Dynamic detection of target genes during gefitinib treatment is crucial for understanding resistance mechanisms.

Purpose of the Study:

  • To investigate the role of Trop2 in gefitinib resistance in NSCLC.
  • To explore the underlying molecular mechanisms by which Trop2 influences gefitinib resistance.
  • To identify potential therapeutic targets for overcoming gefitinib resistance in NSCLC.

Main Methods:

  • Analysis of clinical tissues to correlate Trop2 expression with EGFR mutation and drug resistance.
  • In vitro and in vivo experiments to assess the effect of Trop2 modulation on gefitinib resistance.
  • Investigation of the Trop2-IGF2R-IGF1R-Akt signaling axis and its impact on the TME.

Main Results:

  • Trop2 expression is associated with EGFR mutation and gefitinib resistance in NSCLC clinical samples.
  • Trop2 induces gefitinib resistance by binding IGF2R, promoting the IGF2-IGF1R-Akt axis.
  • Silencing Trop2 combined with an IGF1R inhibitor reduced tumor cell proliferation and remodeled the TME, including macrophage recruitment.

Conclusions:

  • Trop2 plays a critical role in promoting gefitinib resistance in NSCLC.
  • The Trop2-IGF2R-IGF1R-Akt pathway is a key mechanism driving gefitinib resistance and TME remodeling.
  • Targeting Trop2 and IGF1R offers a promising strategy for overcoming gefitinib resistance in NSCLC.
Keywords:
IGF2RNSCLCTMETrop2drug resistancegefitinib

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