| KEAP1-NRF2 pathway as a novel therapeutic target for EGFR-mutant non-small cell lung cancer |
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Jae-Sun Choi, Ph.D.1, Hye-Min Kang, Ph.D.2, Kiyong Na, M.D., Ph.D.3, Jiwon Kim, M.D.4, Tae-Woo Kim, M.D., Ph.D.4, Junyang Jung, M.D., Ph.D.5, Heejin Lim, Ph.D.6, Hyewon Seo, Ph.D.7, Seung Hyeun Lee, M.D., Ph.D.4 |
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, College of Medicine, Kyung Hee University, Kyung Hee University Hospital, Seoul, Republic of Korea
4Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Kyung Hee University, Kyung Hee University Hospital, 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 |
Correspondence:
Seung Hyeun Lee, Tel: +82 2 958 8511, Fax: +82 2 968 1848,
Email: humanmd04@hanmail.net
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Received: 20 July 2024 • Revised: 20 August 2024 • Accepted: 11 September 2024 |
| 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. Co-treatment 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 TKI-resistant lung cancer with EGFR-mutation. Thus, NRF2 modulation may be a novel therapeutic strategy to overcome the resistance to EGFR-tyrosine kinase inhibitors. |
| Key Words:
KEAP1-NRF2 pathway, Epidermal growth factor receptor, Tyrosine kinase inhibitor, Resistance, Brusatol |
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