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Cancer Research and Treatment > Accepted Articles
doi: https://doi.org/10.4143/crt.2021.385    [Accepted]
Acquired Resistance Mechanism of EGFR Kinase Domain Duplication to EGFR TKIs in Non-Small Cell Lung Cancer
Chaelin Lee1, Miso Kim1,2, Dong-Wan Kim1,2,3, Tae Min Kim1,2, Soyeon Kim1,3, Sun-Wha Im4, Yoon Kyung Jeon5, Bhumsuk Keam1,2, Ja-Lok Ku1, Dae Seog Heo1,2
1Cancer Research Institute, Seoul National University, Seoul, Korea
2Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Korea
3Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, Korea
4Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea
5Department of Pathology, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Korea
Correspondence  Dong-Wan Kim ,Tel: 82-2-2072-2995, Fax: 82-2-764-2199, Email: kimdw@snu.ac.kr
Received: March 25, 2021;  Accepted: April 30, 2021.  Published online: May 3, 2021.
*Chaelin Lee and Miso Kim contributed equally to this work.
ABSTRACT
Purpose
Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare and poorly understood oncogenic mutation in non-small cell lung cancer (NSCLC). We aimed to investigate the acquired resistance mechanism of EGFR-KDD against EGFR-TKIs.
Materials and Methods
We identified EGFR-KDD in tumor tissue obtained from a patient with stage IV lung adenocarcinoma and established the patient-derived cell line SNU-4784. We also established several EGFR-KDD Ba/F3 cell lines: EGFR-KDD wild type (EGFR-KDDWT), EGFR-KDD domain 1 T790M (EGFR-KDDD1T), EGFR-KDD domain 2 T790M (EGFR-KDDD2T), and EGFR-KDD both domain T790M (EGFR-KDDBDT). We treated the cells with EGFR tyrosine kinase inhibitors (TKIs) and performed cell viability assays, immunoblot assays, and ENU (N-Ethyl-N-nitrosourea) mutagenesis screening.
Results
In cell viability assays, SNU-4784 cells and EGFR-KDDWT Ba/F3 cells were sensitive to 2nd generation and 3rd generation EGFR TKIs. In contrast, the T790M-positive EGFR-KDD Ba/F3 cell lines (EGFR-KDDT790M) were only sensitive to 3rd generation EGFR TKIs. In ENU mutagenesis screening, we identified the C797S mutation in kinase domain 2 of EGFR-KDDBDT Ba/F3 cells. Based on this finding, we established an EGFR-KDD domain 1 T790M/domain 2 cis-T790M + C797S (EGFR-KDDT/T+C) Ba/F3 model, which was resistant to EGFR TKIs and anti-EGFR monoclonal antibody combined with EGFR TKIs.
Conclusion
Our study reveals that the T790M mutation in EGFR-KDD confers resistance to 1st and 2nd generation EGFR TKIs, but is sensitive to 3rd generation EGFR TKIs. In addition, we identified that the C797S mutation in kinase domain 2 of EGFR-KDDT790M mediates a resistance mechanism against 3rd generation EGFR TKIs.
Key words: EGFR kinase domain duplication, Non-small cell lung cancer, EGFR T790M mutation, EGFR C797S mutation, Acquired resistance
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