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C-IGF1R encoded by cIGF1R acts as a molecular switch to restrict mitophagy of drug-tolerant persister tumour cells in non-small cell lung cancer

Cell Death & Differentiation volume 30, pages 2365–2381 (2023)Cite this article

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Abstract

The clinical efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) is limited by the emergence of drug resistance. We hypothesise that restoring dysregulated circular RNAs under initial treatment with EGFR-TKIs may enhance their effectiveness. Through high-throughput screening, we identify that combining circular RNA IGF1R (cIGF1R) with EGFR-TKIs significantly synergises to suppress tumour regrowth following drug withdrawal. Mechanistically, cIGF1R interacts with RNA helicase A (RHA) to depress insulin-like growth factor 1 receptor (IGF1R) mRNA splicing, negatively regulating the parent IGF1R signalling pathway. This regulation is similar to that of IGF1R inhibitor, which induces drug-tolerant persister (DTP) state with activated mitophagy. The cIGF1R also encodes a peptide C-IGF1R that reduces Parkin-mediated ubiquitination of voltage-dependent anion channel 1 (VDAC1) to restrict mitophagy, acting as a molecular switch that promotes the transition of DTP to apoptosis. Our study shows that combining cIGF1R with EGFR-TKIs efficiently reduces the emergence of DTP.

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Fig. 1: cIGF1R increases the efficacy of EGFR-TKIs.
Fig. 2: cIGF1R interferes with RHA to regulate IGF1R and cIGF1R expression.
Fig. 3: Comparison of the efficacy of EGFR-TKIs plus cIGF1R and EGFR-TKIs plus IGF1R inhibitor (IGF1Ri).
Fig. 4: Cells were apoptotic treated with O plus cIGF1R but entered a DTP state dependent on autophagy under the treatment of O plus IGF1Ri.
Fig. 5: cIGF1R-encoded protein C-IGF1R inhibited the mitophagy of DTP cells under EGFR-TKI and IGF1Ri combination therapy stress.
Fig. 6: C-IGF1R inhibits Parkin-mediated ubiquitination of VDAC1.
Fig. 7: The efficacy of cIGF1R combined with EGFR-TKIs was validated in mice.

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Data availability

CircRNA-seq and RNA-seq data have been deposited in the Gene Expression Omnibus (ncbi.nlm.nih.gov/geo) under accession number GSE211854. The TCGA Research Network (cancergenome.nih.gov) provided the RNA expression data of EGFR-wild-type and EGFR-mutant human LUAD. This document includes source data. All further data supporting the conclusions of this study are accessible upon reasonable request from the corresponding author.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (Grant No. 82372762, 82073211, 81702892, 82002434); The Project of Invigorating Health Care through Science, Technology and Education, Jiangsu Provincial Medical Innovation Team (CXTDA2017002); The Project of Invigorating Health Care through Science, Technology and Education, Jiangsu Provincial Medical Outstanding Talent (JCRCA2016001).

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  1. These authors contributed equally: Hui Wang, Yingkuan Liang, Te Zhang.

Authors and Affiliations

  1. Department of Thoracic Surgery, Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, 42 Baiziting Road, Xuanwu District, Nanjing, 210009, China

    Hui Wang, Yingkuan Liang, Te Zhang, Xuming Song, Yuzhong Chen, Qixing Mao, Wenjie Xia, Bing Chen, Lin Xu & Feng Jiang

  2. Jiangsu Key Laboratory of Molecular and Translational Cancer Research, 42 Baiziting Road, Xuanwu District, Nanjing, 210009, China

    Hui Wang, Te Zhang, Xuming Song, Yuzhong Chen, Qixing Mao, Wenjie Xia, Bing Chen, Lin Xu, Gaochao Dong & Feng Jiang

  3. The Fourth Clinical College of Nanjing Medical University, Nanjing, PR China

    Hui Wang, Xuming Song & Yuzhong Chen

  4. Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215031, China

    Yingkuan Liang & Lin Xu

  5. Collaborative Innovation Centre for Cancer Personalized Medicine, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China

    Te Zhang

  6. Department of Oncology, Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, 42 Baiziting Road, Xuanwu District, Nanjing, 210009, China

    Xinnian Yu

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Contributions

FJ and GD designed experiments and wrote the manuscript. XS performed statistical analysis with the R language. HW, YL, TZ, YC, LX, and XY completed the basic experiment part. BC, WX and QM were responsible for clinical sample collection and subsequent sample delivery. GD and FJ helped to revise the manuscript. All authors read and approved the final manuscript.

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Correspondence to Gaochao Dong or Feng Jiang.

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The research conducted in this manuscript adhered to all applicable ethical regulations. Human tissue samples were obtained from the Department of Thoracic Surgery at Jiangsu Cancer Hospital. Ethical approval was granted by Nanjing Medical University. All mouse research was authorised by the Institutional Animal Care and Use Committee (IACUC) of Nanjing Medical University (IACUC-2209003).

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Wang, H., Liang, Y., Zhang, T. et al. C-IGF1R encoded by cIGF1R acts as a molecular switch to restrict mitophagy of drug-tolerant persister tumour cells in non-small cell lung cancer. Cell Death Differ 30, 2365–2381 (2023). https://doi.org/10.1038/s41418-023-01222-0

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