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

Chun-shuang Ma1, Qian-ming Lv1, Ke-ren Zhang1, Ya-bin Tang1,2, Yu-fei Zhang1, Ying Shen1,2, Hui-min Lei1,2, Liang Zhu1,2
1 Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
2 Shanghai Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China
Correspondence to: Ying Shen:, Hui-min Lei:, Liang Zhu:,
DOI: 10.1038/s41401-020-0443-1
Received: 15 January 2020
Accepted: 13 May 2020
Advance online: 23 July 2020


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.
Keywords: non-small-cell lung cancer; EGFR-TKIs resistance; NRF2; GPX4; SOD2

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