Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Shanghai Collaborative Innovation Center for Translational Medicine, Shanghai, 200025, China.
Acta Pharmacol Sin. 2021 Apr;42(4):613-623. doi: 10.1038/s41401-020-0443-1. Epub 2020 Jul 23.
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.
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）在非小细胞肺癌（NSCLC）的治疗中取得了令人满意的临床效果，但获得性耐药限制了其临床应用。NRF2 已被证明可增强放射治疗和某些化疗诱导的细胞凋亡耐药性。在这项研究中，我们研究了 NRF2 在 EGFR-TKI 耐药中的作用。我们发现，由于 NRF2 蛋白降解缓慢，一组 EGFR-TKI 耐药性 NSCLC 细胞系中 NRF2 蛋白水平显著增加。NRF2 敲低克服了 HCC827ER 和 HCC827GR 细胞对 EGFR-TKIs 的耐药性。此外，我们证明 NRF2 通过上调 GPX4 和 SOD2 以及抑制 GPX4 和 SOD2 赋予 HCC827 细胞对 EGFR-TKIs 的耐药性，而抑制 GPX4 和 SOD2 可逆转对 EGFR-TKIs 的耐药性。因此，我们得出结论，靶向 NRF2-GPX4/SOD2 途径是克服 EGFR-TKIs 耐药性的一种潜在策略。
