Identification of GPX4 as a therapeutic target for lung adenocarcinoma after EGFR-TKI resistance

Zhang, Chuanfen and Wang, Chunmei and Yang, Zhenyu and Bai, Yuquan and Shukuya, Takehito and Poh, Mau Ern and Ekman, Simon and Li, Jian and Xu, Yuyang and Deng, Senyi (2022) Identification of GPX4 as a therapeutic target for lung adenocarcinoma after EGFR-TKI resistance. Translational Lung Cancer Research, 11 (5). 786+. ISSN 2218-6751, DOI

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Tyrosine kinase inhibitor (TKI) treatment has significantly improved the prognosis of oncogenic-driven lung adenocarcinoma (LUAD). However, drug resistance limits the long-term benefits of patients. Therefore, there is a pressing need to explore the mechanism of TKI resistance and identify new therapeutic targets. It is possible to overcome TKI resistance by inducing tumor cell death through a new process called ferroptosis. Aberrations in ferroptosis, which is a kind of regulated cell death (RCD), has been confirmed to be involved in the development and progression of multiple tumors, and is closely related to patient survival. At present, the role of ferroptosis in TKI resistance remains unclear. Methods: Ferroptosis-related factors were isolated by expression characteristics analysis based on the multiomics data of LUADs and normal lung tissues from The Cancer Genome Atlas (TCGA) database. Next, expression of selected ferroptosis-related factors and prognosis were analyzed. Subsequently, the differences in the expression of selected ferroptosis-related factors before and after TKI resistance on a variety of LUAD cell lines were analyzed to identify the factors that were involved in TKI resistance. Finally, the therapeutic effects were confirmed in vitro by targeting the selected ferroptosis-related factors with small molecule compounds. Results: Glutathione Peroxidase 4 (GPX4), a ferroptosis-related factor, was up-regulated in tumor tissue of LUADs, and correlated with the prognosis of patients. By detecting the expression change of GPX4 before and after TKI resistance in a variety of LUAD cell lines, we confirmed that the inhibition of GPX4 could overcome epidermal growth factor receptor (EGFR)-TKI resistance by inducing ferroptosis. Conclusions: GPX4 could serve as a novel therapeutic target for EGFR-TKI resistance in LUAD.

Item Type: Article
Funders: 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University [ZYGD18021] [ZYJC18009]
Uncontrolled Keywords: Ferroptosis; Lung adenocarcinoma (LUAD); TKI resistance; GPX4; Target
Subjects: R Medicine
Divisions: Faculty of Medicine
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 25 Sep 2023 02:11
Last Modified: 25 Sep 2023 02:11

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