KEAP1-NRF2 Pathway as a Novel Therapeutic Target for EGFR-Mutant Non-small Cell Lung Cancer
Background Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor erythroid-2-related factor 2 (NRF2) pathway is a major regulator protecting cells from oxidative and metabolic stress. Studies have revealed that this pathway is involved in mediating resistance to cytotoxic chemotherapy and immun...
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The Korean Academy of Tuberculosis and Respiratory Diseases
2025-01-01
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| Series: | Tuberculosis and Respiratory Diseases |
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| Online Access: | http://e-trd.org/upload/pdf/trd-2024-0087.pdf |
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| author | Jae-Sun Choi Hye-Min Kang Kiyong Na Jiwon Kim Tae-Woo Kim Junyang Jung Heejin Lim Hyewon Seo Seung Hyeun Lee |
| author_facet | Jae-Sun Choi Hye-Min Kang Kiyong Na Jiwon Kim Tae-Woo Kim Junyang Jung Heejin Lim Hyewon Seo Seung Hyeun Lee |
| author_sort | Jae-Sun Choi |
| collection | DOAJ |
| description | Background Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor erythroid-2-related factor 2 (NRF2) pathway is a major regulator protecting cells from oxidative and metabolic stress. Studies have revealed that this pathway is involved in mediating resistance to cytotoxic chemotherapy and immunotherapy; however, its implications in oncogene-addicted tumors are largely unknown. This study aimed to elucidate whether this pathway could be a potential therapeutic target for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Methods We measured the baseline expression of NRF2 using EGFR-mutant parental cells and acquired gefitinib resistant cells. We investigated whether NRF2 inhibition affected cell death in vitro and tumor growth in vivo using a xenograft mouse model, and compared the transcriptional changes before and after NRF2 inhibition. Results Baseline NRF2 expression was enhanced in PC9 and PC9 with gefitinib resistance (PC9/GR) cells than in other cell lines, with a more prominent expression in PC9/GR. The NRF2 inhibitor induced NRF2 downregulation and cell death in a dose-dependent manner. Cotreatment with an NRF2 inhibitor enhanced osimertinib-induced cell death in vitro, and potentiated tumor growth inhibition in a PC9/GR xenograft model. Finally, RNA sequencing revealed that NRF2 inhibition resulted in the altered expression of multiple genes involved in various signaling pathways. Conclusion We identified that NRF2 inhibition enhanced cell death and inhibited tumor growth in tyrosine kinase inhibitor (TKI)-resistant lung cancer with EGFR-mutation. Thus, NRF2 modulation may be a novel therapeutic strategy to overcome the resistance to EGFR-TKIs. |
| format | Article |
| id | doaj-art-78bbf3ef16ce4c508ec9b4bc73ec61ec |
| institution | OA Journals |
| issn | 1738-3536 2005-6184 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | The Korean Academy of Tuberculosis and Respiratory Diseases |
| record_format | Article |
| series | Tuberculosis and Respiratory Diseases |
| spelling | doaj-art-78bbf3ef16ce4c508ec9b4bc73ec61ec2025-08-20T02:25:44ZengThe Korean Academy of Tuberculosis and Respiratory DiseasesTuberculosis and Respiratory Diseases1738-35362005-61842025-01-0188113814910.4046/trd.2024.00874896KEAP1-NRF2 Pathway as a Novel Therapeutic Target for EGFR-Mutant Non-small Cell Lung CancerJae-Sun Choi0Hye-Min Kang1Kiyong Na2Jiwon Kim3Tae-Woo Kim4Junyang Jung5Heejin Lim6Hyewon Seo7Seung Hyeun Lee8 Clinical Research Institute, Kyung Hee University Medical Center, Seoul, Republic of Korea Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Kyung Hee University, Seoul, Republic of Korea Department of Pathology, Kyung Hee University Hospital, College of Medicine, Kyung Hee University, Seoul, Republic of Korea Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Kyung Hee University Hospital, College of Medicine, Kyung Hee University, Seoul, Republic of Korea Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Kyung Hee University Hospital, College of Medicine, Kyung Hee University, Seoul, Republic of Korea Department of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea Center for Scientific Instrumentation, Korea Basic Science Institute, Cheongju, Republic of Korea New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Kyung Hee University Hospital, College of Medicine, Kyung Hee University, Seoul, Republic of KoreaBackground Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor erythroid-2-related factor 2 (NRF2) pathway is a major regulator protecting cells from oxidative and metabolic stress. Studies have revealed that this pathway is involved in mediating resistance to cytotoxic chemotherapy and immunotherapy; however, its implications in oncogene-addicted tumors are largely unknown. This study aimed to elucidate whether this pathway could be a potential therapeutic target for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Methods We measured the baseline expression of NRF2 using EGFR-mutant parental cells and acquired gefitinib resistant cells. We investigated whether NRF2 inhibition affected cell death in vitro and tumor growth in vivo using a xenograft mouse model, and compared the transcriptional changes before and after NRF2 inhibition. Results Baseline NRF2 expression was enhanced in PC9 and PC9 with gefitinib resistance (PC9/GR) cells than in other cell lines, with a more prominent expression in PC9/GR. The NRF2 inhibitor induced NRF2 downregulation and cell death in a dose-dependent manner. Cotreatment with an NRF2 inhibitor enhanced osimertinib-induced cell death in vitro, and potentiated tumor growth inhibition in a PC9/GR xenograft model. Finally, RNA sequencing revealed that NRF2 inhibition resulted in the altered expression of multiple genes involved in various signaling pathways. Conclusion We identified that NRF2 inhibition enhanced cell death and inhibited tumor growth in tyrosine kinase inhibitor (TKI)-resistant lung cancer with EGFR-mutation. Thus, NRF2 modulation may be a novel therapeutic strategy to overcome the resistance to EGFR-TKIs.http://e-trd.org/upload/pdf/trd-2024-0087.pdfkeap1-nrf2 pathwayepidermal growth factor receptortyrosine kinase inhibitorresistancebrusatol |
| spellingShingle | Jae-Sun Choi Hye-Min Kang Kiyong Na Jiwon Kim Tae-Woo Kim Junyang Jung Heejin Lim Hyewon Seo Seung Hyeun Lee KEAP1-NRF2 Pathway as a Novel Therapeutic Target for EGFR-Mutant Non-small Cell Lung Cancer Tuberculosis and Respiratory Diseases keap1-nrf2 pathway epidermal growth factor receptor tyrosine kinase inhibitor resistance brusatol |
| title | KEAP1-NRF2 Pathway as a Novel Therapeutic Target for EGFR-Mutant Non-small Cell Lung Cancer |
| title_full | KEAP1-NRF2 Pathway as a Novel Therapeutic Target for EGFR-Mutant Non-small Cell Lung Cancer |
| title_fullStr | KEAP1-NRF2 Pathway as a Novel Therapeutic Target for EGFR-Mutant Non-small Cell Lung Cancer |
| title_full_unstemmed | KEAP1-NRF2 Pathway as a Novel Therapeutic Target for EGFR-Mutant Non-small Cell Lung Cancer |
| title_short | KEAP1-NRF2 Pathway as a Novel Therapeutic Target for EGFR-Mutant Non-small Cell Lung Cancer |
| title_sort | keap1 nrf2 pathway as a novel therapeutic target for egfr mutant non small cell lung cancer |
| topic | keap1-nrf2 pathway epidermal growth factor receptor tyrosine kinase inhibitor resistance brusatol |
| url | http://e-trd.org/upload/pdf/trd-2024-0087.pdf |
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