2. Academic Validation
  3. Ferritinophagy mediates adaptive resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer

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

  • Nat Commun. 2024 May 17;15(1):4195. doi: 10.1038/s41467-024-48433-8.
Hui Wang # 1 2 3,  Qianfan Hu # 1 2 3,  Yuzhong Chen # 2 4,  Xing Huang # 5,  Yipeng Feng 2 3,  Yuanjian Shi 2 3,  Rutao Li 6,  Xuewen Yin 2,  Xuming Song 2 3,  Yingkuan Liang 1,  Te Zhang 2 3,  Lin Xu 1 2 3 7,  Gaochao Dong 8 9,  Feng Jiang 10 11 12
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Xuanwu District, Nanjing, China.
  • 2 Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Xuanwu District, Nanjing, China.
  • 3 The Fourth Clinical College of Nanjing Medical University, Nanjing, PR China.
  • 4 Department of Oncology, Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Xuanwu District, Nanjing, China.
  • 5 Department of Pathology, Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Xuanwu District, Nanjing, China.
  • 6 Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 7 Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Jiangning District, Nanjing, China.
  • 8 Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Xuanwu District, Nanjing, China. gaochao_dong@njmu.edu.cn.
  • 9 The Fourth Clinical College of Nanjing Medical University, Nanjing, PR China. gaochao_dong@njmu.edu.cn.
  • 10 Department of Thoracic Surgery, Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Xuanwu District, Nanjing, China. fengjiang_nj@njmu.edu.cn.
  • 11 Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Xuanwu District, Nanjing, China. fengjiang_nj@njmu.edu.cn.
  • 12 The Fourth Clinical College of Nanjing Medical University, Nanjing, PR China. fengjiang_nj@njmu.edu.cn.
  • # Contributed equally.
PMID: 38760351 DOI: 10.1038/s41467-024-48433-8
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.

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