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Ferritinophagy mediates adaptive resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer

Author

Listed:
  • Hui Wang

    (Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research
    Jiangsu Key Laboratory of Molecular and Translational Cancer Research
    The Fourth Clinical College of Nanjing Medical University)

  • Qianfan Hu

    (Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research
    Jiangsu Key Laboratory of Molecular and Translational Cancer Research
    The Fourth Clinical College of Nanjing Medical University)

  • Yuzhong Chen

    (Jiangsu Key Laboratory of Molecular and Translational Cancer Research
    Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research)

  • Xing Huang

    (Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research)

  • Yipeng Feng

    (Jiangsu Key Laboratory of Molecular and Translational Cancer Research
    The Fourth Clinical College of Nanjing Medical University)

  • Yuanjian Shi

    (Jiangsu Key Laboratory of Molecular and Translational Cancer Research
    The Fourth Clinical College of Nanjing Medical University)

  • Rutao Li

    (The First Affiliated Hospital of Soochow University)

  • Xuewen Yin

    (Jiangsu Key Laboratory of Molecular and Translational Cancer Research)

  • Xuming Song

    (Jiangsu Key Laboratory of Molecular and Translational Cancer Research
    The Fourth Clinical College of Nanjing Medical University)

  • Yingkuan Liang

    (Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research)

  • Te Zhang

    (Jiangsu Key Laboratory of Molecular and Translational Cancer Research
    The Fourth Clinical College of Nanjing Medical University)

  • Lin Xu

    (Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research
    Jiangsu Key Laboratory of Molecular and Translational Cancer Research
    The Fourth Clinical College of Nanjing Medical University
    Nanjing Medical University)

  • Gaochao Dong

    (Jiangsu Key Laboratory of Molecular and Translational Cancer Research
    The Fourth Clinical College of Nanjing Medical University)

  • Feng Jiang

    (Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research
    Jiangsu Key Laboratory of Molecular and Translational Cancer Research
    The Fourth Clinical College of Nanjing Medical University)

Abstract

Osimertinib (Osi) is a widely used epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). However, the emergence of resistance is inevitable, partly due to the gradual evolution of adaptive resistant cells during initial treatment. Here, we find that Osi treatment rapidly triggers adaptive resistance in tumor cells. Metabolomics analysis reveals a significant enhancement of oxidative phosphorylation (OXPHOS) in Osi adaptive-resistant cells. Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA4-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy.

Suggested Citation

  • Hui Wang & Qianfan Hu & Yuzhong Chen & Xing Huang & Yipeng Feng & Yuanjian Shi & Rutao Li & Xuewen Yin & Xuming Song & Yingkuan Liang & Te Zhang & Lin Xu & Gaochao Dong & Feng Jiang, 2024. "Ferritinophagy mediates adaptive resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48433-8
    DOI: 10.1038/s41467-024-48433-8
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    References listed on IDEAS

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    1. Ana Luísa Correia & Joao C. Guimaraes & Priska Auf der Maur & Duvini De Silva & Marcel P. Trefny & Ryoko Okamoto & Sandro Bruno & Alexander Schmidt & Kirsten Mertz & Katrin Volkmann & Luigi Terraccian, 2021. "Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy," Nature, Nature, vol. 594(7864), pages 566-571, June.
    2. Yuying Tan & Junjie Li & Guangyuan Zhao & Kai-Chih Huang & Horacio Cardenas & Yinu Wang & Daniela Matei & Ji-Xin Cheng, 2022. "Metabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation in platinum-resistant cancer cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
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