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

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 () and Feng Jiang ()
Additional contact information
Hui Wang: Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research
Qianfan Hu: Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research
Yuzhong Chen: Jiangsu Key Laboratory of Molecular and Translational 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
Yuanjian Shi: Jiangsu Key Laboratory of Molecular and Translational Cancer Research
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
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
Lin Xu: Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research
Gaochao Dong: Jiangsu Key Laboratory of Molecular and Translational Cancer Research
Feng Jiang: Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-48433-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48433-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-48433-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().