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Identification of GPX4 as a therapeutic target for lung adenocarcinoma after EGFR-TKI resistance

Chuanfen Zhang1, Chunmei Wang1,2, Zhenyu Yang1

  • 1Institute of Thoracic Oncology and Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China.

Translational Lung Cancer Research
|June 13, 2022
PubMed
Abstract

Insights

Targeting Glutathione Peroxidase 4 (GPX4) can overcome resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma. Inhibiting GPX4 induces ferroptosis, offering a new therapeutic strategy for patients with TKI-resistant lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Research

Background:

  • Tyrosine kinase inhibitor (TKI) treatment improves outcomes for lung adenocarcinoma (LUAD) but drug resistance remains a challenge.
  • Ferroptosis, a form of regulated cell death, is implicated in various cancers, but its role in TKI resistance is unclear.
  • Identifying novel therapeutic targets is crucial for overcoming TKI resistance in LUAD.

Purpose of the Study:

  • To investigate the role of ferroptosis-related factors in TKI resistance in LUAD.
  • To identify potential therapeutic targets for overcoming EGFR-TKI resistance.

Main Methods:

  • Multi-omics data from TCGA were used to identify ferroptosis-related factors in LUAD.
  • Expression analysis of these factors was performed in LUAD tissues and cell lines before and after TKI resistance.
  • In vitro studies evaluated the therapeutic potential of targeting identified factors.

Main Results:

  • Glutathione Peroxidase 4 (GPX4) was found to be upregulated in LUAD and correlated with patient prognosis.
  • GPX4 inhibition was shown to overcome EGFR-TKI resistance by inducing ferroptosis in LUAD cell lines.
  • GPX4 expression changes were observed in LUAD cells developing TKI resistance.

Conclusions:

  • Glutathione Peroxidase 4 (GPX4) is a key ferroptosis-related factor involved in EGFR-TKI resistance in LUAD.
  • GPX4 represents a promising novel therapeutic target for overcoming TKI resistance in lung adenocarcinoma.
  • Targeting GPX4 could offer a new strategy to improve treatment outcomes for LUAD patients resistant to EGFR-TKIs.
Keywords:
FerroptosisGPX4TKI resistancelung adenocarcinoma (LUAD)target

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