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Acquired Resistance Mechanism of EGFR Kinase Domain Duplication to EGFR TKIs in Non–Small Cell Lung Cancer

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dc.contributor.authorLee, Chaelin-
dc.contributor.authorKim, Miso-
dc.contributor.authorKim, Dong-Wan-
dc.contributor.authorKim, Tae Min-
dc.contributor.authorKim, Soyeon-
dc.contributor.authorIm, Sun-Wha-
dc.contributor.authorJeon, Yoon Kyung-
dc.contributor.authorKeam, Bhumsuk-
dc.contributor.authorKu, Ja-Lok-
dc.contributor.authorHeo, Dae Seog-
dc.date.accessioned2022-06-24T08:26:47Z-
dc.date.available2022-06-24T08:26:47Z-
dc.date.created2022-05-13-
dc.date.created2022-05-13-
dc.date.created2022-05-13-
dc.date.created2022-05-13-
dc.date.created2022-05-13-
dc.date.issued2022-01-
dc.identifier.citationCancer Research and Treatment, Vol.54 No.1, pp.140-149-
dc.identifier.issn1598-2998-
dc.identifier.urihttps://hdl.handle.net/10371/184080-
dc.description.abstractCopyright © 2022 by the Korean Cancer Association.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.-
dc.language영어-
dc.publisher대한암학회-
dc.titleAcquired Resistance Mechanism of EGFR Kinase Domain Duplication to EGFR TKIs in Non–Small Cell Lung Cancer-
dc.typeArticle-
dc.identifier.doi10.4143/CRT.2021.385-
dc.citation.journaltitleCancer Research and Treatment-
dc.identifier.wosid000788852400014-
dc.identifier.scopusid2-s2.0-85123642229-
dc.citation.endpage149-
dc.citation.number1-
dc.citation.startpage140-
dc.citation.volume54-
dc.identifier.kciidART002802656-
dc.description.isOpenAccessY-
dc.contributor.affiliatedAuthorKim, Dong-Wan-
dc.contributor.affiliatedAuthorJeon, Yoon Kyung-
dc.contributor.affiliatedAuthorKu, Ja-Lok-
dc.contributor.affiliatedAuthorHeo, Dae Seog-
dc.type.docTypeArticle-
dc.description.journalClass1-
dc.subject.keywordPlusCLINICAL-RESPONSE-
dc.subject.keywordPlusMUTATIONS-
dc.subject.keywordPlusTHERAPY-
dc.subject.keywordPlusPATIENT-
dc.subject.keywordPlusOSIMERTINIB-
dc.subject.keywordPlusACTIVATION-
dc.subject.keywordPlusDOCETAXEL-
dc.subject.keywordPlusERLOTINIB-
dc.subject.keywordPlusAZD9291-
dc.subject.keywordPlusKDD-
dc.subject.keywordAuthorAcquired resistance-
dc.subject.keywordAuthorEGFR C797S mutation-
dc.subject.keywordAuthorEGFR kinase domain duplication-
dc.subject.keywordAuthorEGFR T790M mutation-
dc.subject.keywordAuthorNon–small cell lung carcinoma-
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