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Identification of GPX4 as a therapeutic target for lung adenocarcinoma after EGFR-TKI resistance
BACKGROUND: 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 identi...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
AME Publishing Company
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9186177/ https://www.ncbi.nlm.nih.gov/pubmed/35693278 http://dx.doi.org/10.21037/tlcr-22-318 |
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author | Zhang, Chuanfen Wang, Chunmei Yang, Zhenyu Bai, Yuquan Shukuya, Takehito Poh, Mau-Ern Ekman, Simon Li, Jian Xu, Yuyang Deng, Senyi |
author_facet | Zhang, Chuanfen Wang, Chunmei Yang, Zhenyu Bai, Yuquan Shukuya, Takehito Poh, Mau-Ern Ekman, Simon Li, Jian Xu, Yuyang Deng, Senyi |
author_sort | Zhang, Chuanfen |
collection | PubMed |
description | BACKGROUND: 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 multi-omics 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. |
format | Online Article Text |
id | pubmed-9186177 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | AME Publishing Company |
record_format | MEDLINE/PubMed |
spelling | pubmed-91861772022-06-11 Identification of GPX4 as a therapeutic target for lung adenocarcinoma after EGFR-TKI resistance Zhang, Chuanfen Wang, Chunmei Yang, Zhenyu Bai, Yuquan Shukuya, Takehito Poh, Mau-Ern Ekman, Simon Li, Jian Xu, Yuyang Deng, Senyi Transl Lung Cancer Res Original Article BACKGROUND: 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 multi-omics 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. AME Publishing Company 2022-05 /pmc/articles/PMC9186177/ /pubmed/35693278 http://dx.doi.org/10.21037/tlcr-22-318 Text en 2022 Translational Lung Cancer Research. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Original Article Zhang, Chuanfen Wang, Chunmei Yang, Zhenyu Bai, Yuquan Shukuya, Takehito Poh, Mau-Ern Ekman, Simon Li, Jian Xu, Yuyang Deng, Senyi Identification of GPX4 as a therapeutic target for lung adenocarcinoma after EGFR-TKI resistance |
title | Identification of GPX4 as a therapeutic target for lung adenocarcinoma after EGFR-TKI resistance |
title_full | Identification of GPX4 as a therapeutic target for lung adenocarcinoma after EGFR-TKI resistance |
title_fullStr | Identification of GPX4 as a therapeutic target for lung adenocarcinoma after EGFR-TKI resistance |
title_full_unstemmed | Identification of GPX4 as a therapeutic target for lung adenocarcinoma after EGFR-TKI resistance |
title_short | Identification of GPX4 as a therapeutic target for lung adenocarcinoma after EGFR-TKI resistance |
title_sort | identification of gpx4 as a therapeutic target for lung adenocarcinoma after egfr-tki resistance |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9186177/ https://www.ncbi.nlm.nih.gov/pubmed/35693278 http://dx.doi.org/10.21037/tlcr-22-318 |
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