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NRF2-GPX4/SOD2 axis imparts resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer cells

Abstract

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have achieved satisfactory clinical effects in the therapy of non-small cell lung cancer (NSCLC), but acquired resistance limits their clinical application. NRF2 has been shown to enhance the resistance to apoptosis induced by radiotherapy and some chemotherapy. In this study, we investigated the role of NRF2 in resistance to EGFR-TKIs. We showed that NRF2 protein levels were markedly increased in a panel of EGFR-TKI-resistant NSCLC cell lines due to slow degradation of NRF2 protein. NRF2 knockdown overcame the resistance to EGFR-TKIs in HCC827ER and HCC827GR cells. Furthermore, we demonstrated that NRF2 imparted EGFR-TKIs resistance in HCC827 cells via upregulation of GPX4 and SOD2, and suppression of GPX4 and SOD2 reversed resistance to EGFR-TKIs. Thus, we conclude that targeting NRF2-GPX4/SOD2 pathway is a potential strategy for overcoming resistance to EGFR-TKIs.

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Fig. 1: EGFR-TKI-resistant cells upregulate NRF2.
Fig. 2: NRF2 knockdown selectively inhibits the proliferation of EGFR-TKI-resistant cells.
Fig. 3: Knockdown of NRF2 reverses EMT and inhibits the migration ability of resistant cells.
Fig. 4: EGFR-TKI-resistant cells upregulate the antioxidant proteins GPX4 and SOD2.
Fig. 5: Inhibition of both SOD2 or NRF2 reverses EMT and impairs the migration ability of resistant cells.
Fig. 6: NRF2-induced resistance to EGFR-TKIs depends on SOD2 and GPX4.
Fig. 7: Targeting the NRF2-GPX4/SOD2 pathway resensitizes resistant cells to EGFR-TKIs.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81872882, 81573018) and the Shanghai Municipal Science Foundation (No. 14YZ032, 2013-52).

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CSM and QML substantially contributed to designing the study, performing experiments, analyzing the data, and writing the manuscript. KRZ, YBT, and YFZ performed experiments and analyzed the data. LZ, HML, and YS conceived and designed the study and experiments, assembled and interpreted the data, wrote the manuscript, and approved the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ying Shen or Hui-min Lei or Liang Zhu.

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The authors declare no competing interests.

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Ma, Cs., Lv, Qm., Zhang, Kr. et al. NRF2-GPX4/SOD2 axis imparts resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer cells. Acta Pharmacol Sin 42, 613–623 (2021). https://doi.org/10.1038/s41401-020-0443-1

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Keywords

  • non-small-cell lung cancer
  • EGFR-TKIs resistance
  • NRF2
  • GPX4
  • SOD2

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