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Updated: Aug 11, 2025

Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
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Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics

Published on: March 15, 2024

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Carbonic Anhydrase IX Controls Vulnerability to Ferroptosis in Gefitinib-Resistant Lung Cancer

Chen Zhang1, Xiyi Lu1, Xinyin Liu1

  • 1Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, Jiangsu, China.

Oxidative Medicine and Cellular Longevity
|February 10, 2023
PubMed

Insights

Carbonic anhydrase IX (CA9) drives resistance to EGFR-TKI therapy in lung cancer by blocking ferroptosis. Targeting CA9 restores ferroptosis, offering a new strategy to overcome gefitinib resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) is a significant challenge in lung cancer treatment.
  • Ferroptosis-inducing therapy shows potential against EGFR-TKI resistant cancers but lacks clinical translation.

Purpose of the Study:

  • To investigate the role of carbonic anhydrase IX (CA9) in gefitinib-resistant lung cancer.
  • To explore CA9 as a therapeutic target to overcome resistance by inducing ferroptosis.

Main Methods:

  • Upregulation of CA9 in gefitinib-resistant lung cancer cells was identified.
  • Cell viability, reactive oxygen species (ROS), and labile iron levels were measured after erastin treatment.
  • Mechanisms of CA9-mediated ferroptosis resistance were investigated, including transferrin endocytosis and ferritin stabilization.

Main Results:

  • CA9 was found to confer resistance to ferroptosis-inducing drugs by inhibiting transferrin endocytosis and stabilizing ferritin.
  • Targeting CA9 promoted iron uptake and release, inducing ferroptosis in gefitinib-resistant cells.
  • A CA9 inhibitor enhanced cisplatin's ferroptosis-inducing effect, leading to the elimination of resistant cells in heterogeneous tumors.

Conclusions:

  • CA9 plays a critical role in mediating resistance to ferroptosis in lung cancer.
  • Targeting CA9 is a promising therapeutic strategy to enhance the efficacy of gefitinib and overcome treatment resistance by inducing ferroptosis.

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