期刊
ACTA PHARMACOLOGICA SINICA
卷 42, 期 4, 页码 613-623出版社
NATURE PUBL GROUP
DOI: 10.1038/s41401-020-0443-1
关键词
non-small-cell lung cancer; EGFR-TKIs resistance; NRF2; GPX4; SOD2
资金
- National Natural Science Foundation of China [81872882, 81573018]
- Shanghai Municipal Science Foundation [14YZ032, 2013-52]
The study demonstrates the crucial role of NRF2 in mediating resistance to EGFR-TKIs by regulating the expression of GPX4 and SOD2. Targeting the NRF2-GPX4/SOD2 pathway may be a potential strategy for overcoming resistance to EGFR-TKIs, providing a novel approach in treating NSCLC.
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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