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Updated: May 11, 2026

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
09:38

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Published on: August 11, 2017

TGM2-TUFM promotes acquired resistance to EGFR-TKIs in EGFR-mutated NSCLC through p62-mediated lipophagy

Jie Shen1, Lanying Gou1, Yujie Sun1

  • 1Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.

Respiratory Research
|May 9, 2026
PubMed
Abstract

Insights

Transglutaminase 2 (TGM2) drives resistance to EGFR-TKIs in non-small cell lung cancer (NSCLC) by promoting lipophagy and fatty acid oxidation. Inhibiting TGM2 or its downstream pathways may overcome this acquired resistance in EGFR-mutated NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a major challenge in treating advanced non-small cell lung cancer (NSCLC) with EGFR mutations.
  • Understanding the mechanisms of this resistance is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate the role of Transglutaminase 2 (TGM2) in acquired resistance to EGFR-TKIs in EGFR-mutated NSCLC.
  • To elucidate the molecular mechanisms by which TGM2 contributes to drug resistance.

Main Methods:

  • Transcriptome sequencing and GDC database analysis were used to identify differential genes and analyze prognosis.
  • Quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry were employed to assess TGM2 expression.
  • Cell viability assays (CCK-8), flow cytometry, mouse xenograft models, gene enrichment analysis, and mass spectrometry were utilized to verify TGM2's effects and mechanisms.

Main Results:

  • TGM2 was found to be highly expressed in EGFR-TKI-resistant NSCLC cells and tissues, correlating with shorter survival.
  • Overexpression of TGM2 conferred resistance to EGFR-TKIs in both cell culture and xenograft models.
  • TGM2 promotes lipophagy and fatty acid oxidation by inhibiting TUFM degradation, enhancing drug resistance. TGM2 also facilitates p62 body formation, promoting lipid droplet breakdown via perilipin 2.

Conclusions:

  • TGM2 plays a significant role in acquired EGFR-TKI resistance in NSCLC.
  • TGM2 represents a potential therapeutic target and a predictive biomarker for acquired EGFR-TKI resistance in EGFR-mutated NSCLC.
Keywords:
EGFR-TKI resistanceLipophagyNon-small cell lung cancerTGM2

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