Tuberc Respir Dis.
2025 Jan;88(1):138-149. 10.4046/trd.2024.0087.
KEAP1-NRF2 Pathway as a Novel Therapeutic Target for EGFR-Mutant Non-small Cell Lung Cancer
- Affiliations
-
- 1Clinical Research Institute, Kyung Hee University Medical Center, Seoul, Republic of Korea
- 2Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
- 3Department of Pathology, Kyung Hee University Hospital, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
- 4Division 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
- 5Department of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
- 6Center for Scientific Instrumentation, Korea Basic Science Institute, Cheongju, Republic of Korea
- 7New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea
- KMID: 2562636
- DOI: http://doi.org/10.4046/trd.2024.0087
Abstract
- 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.
- Full Text Links
-
- Actions
-
Cited
- CITED
-
- Close
- Share
-
- Similar articles
-
- Dysregulation of NRF2 in Cancer: from Molecular Mechanisms to Therapeutic Opportunities
- Impact of Nrf2 overexpression on cholangiocarcinoma treatment and clinical prognosis
- Molecularly Targeted Therapy for Lung Cancer : Recent Topics
- Quercetin induces cell death by caspase-dependent and p38 MAPK pathway in EGFR mutant lung cancer cells
- Nuclear Factor Erythroid 2-Related Factor 2/Kelch-Like ECH-Associated Protein 1 as a Predictor of Prognosis and Radiotherapy Resistance in Patients With Locally Advanced Rectal Cancer: A Prospective Analysis
