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Preclinical Modeling of Osimertinib for NSCLC With EGFR Exon 20 Insertion Mutations
DC Field | Value | Language |
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dc.contributor.author | Lee, Yusoo | - |
dc.contributor.author | Kim, Tae Min | - |
dc.contributor.author | Kim, Dong-Wan | - |
dc.contributor.author | Kim, Soyeon | - |
dc.contributor.author | Kim, Miso | - |
dc.contributor.author | Keam, Bhumsuk | - |
dc.contributor.author | Ku, Ja-Lok | - |
dc.contributor.author | Heo, Dae Seog | - |
dc.date.accessioned | 2021-01-31T08:06:53Z | - |
dc.date.available | 2021-01-31T08:06:53Z | - |
dc.date.created | 2019-11-25 | - |
dc.date.issued | 2019-09 | - |
dc.identifier.citation | Journal of Thoracic Oncology, Vol.14 No.9, pp.1556-1566 | - |
dc.identifier.issn | 1556-0864 | - |
dc.identifier.other | 86808 | - |
dc.identifier.uri | https://hdl.handle.net/10371/171816 | - |
dc.description.abstract | Introduction: NSCLC with EGFR exon 20 insertion mutations is the third most common type of EGFR-mutant NSCLC and is resistant to EGFR tyrosine kinase inhibitors (TKIs). This study was conducted to evaluate the efficacies of first-to third-generation EGFR TKIs against NSCLC cells harboring EGFR exon 20 insertion mutations. Methods: We developed seven EGFR exon 20 insertion-mutant Ba/F3 models and one patient-derived NSCLC (SNU-3173) of subtypes A763insFQEA, V769insASV, D770insSVD, D770insNPG, P772insPR, H773insH, H773insNPH, and H773insAH. Cell viability assays, immunoblotting, and N-ethyl-N-nitrosourea mutagenesis screenings were performed. EGFR exon 20 insertion-mutant structures and couplings with osimertinib, a third-generation EGFR TKI, were modeled and compared. Results: EGFR exon 20 insertion-mutant NSCLC cells, excluding EGFR A763insFQEA, were resistant to first-generation EGFR TKIs (concentration that inhibits 50% [IC50], 1.1 +/- 0.067 to 5.4 +/- 0.115 mu M). Mutants were sensitive to second-generation EGFR TKIs (IC50, 0.02 +/- 0.0002 to 161.8 +/- 18.7nM), except EGFR H773insH (IC50, 46.3 +/- 8.0 to 352.5 +/- 22.7nM). The IC50 ratios for mutant to wild-type cells were higher than those for third-generation EGFR TKIs. Third-generation EGFR TKI osimertinib was highly potent against EGFR exon 20 insertion-mutant cells (IC50, 14.7-62.7 nM), including EGFR H773insH, and spared wild-type EGFR cells. N-ethyl-N-nitrosourea mutagenesis screening of EGFR exon 20 insertion-mutant Ba/F3 cells showed various second sites for EGFR mutations, mostly at exons 20 and 21, including E762K, P794S, and G796D. In addition, osimertinib-resistant cells were established by stepwise exposure to osimertinib and harbored EGFR E762K mutation. Conclusions: Osimertinib is active against EGFR exon 20 insertion- mutant NSCLC and flexibly binds within drug-binding pockets in preclinical models. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. | - |
dc.language | 영어 | - |
dc.publisher | Elsevier Inc. | - |
dc.title | Preclinical Modeling of Osimertinib for NSCLC With EGFR Exon 20 Insertion Mutations | - |
dc.type | Article | - |
dc.contributor.AlternativeAuthor | 김동완 | - |
dc.contributor.AlternativeAuthor | 구자록 | - |
dc.identifier.doi | 10.1016/j.jtho.2019.05.006 | - |
dc.citation.journaltitle | Journal of Thoracic Oncology | - |
dc.identifier.wosid | 000482190300026 | - |
dc.identifier.scopusid | 2-s2.0-85068119415 | - |
dc.citation.endpage | 1566 | - |
dc.citation.number | 9 | - |
dc.citation.startpage | 1556 | - |
dc.citation.volume | 14 | - |
dc.identifier.sci | 000482190300026 | - |
dc.description.isOpenAccess | Y | - |
dc.contributor.affiliatedAuthor | Kim, Dong-Wan | - |
dc.contributor.affiliatedAuthor | Ku, Ja-Lok | - |
dc.contributor.affiliatedAuthor | Heo, Dae Seog | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.subject.keywordPlus | CELL LUNG-CANCER | - |
dc.subject.keywordPlus | RESISTANCE | - |
dc.subject.keywordPlus | KINASE | - |
dc.subject.keywordPlus | AFATINIB | - |
dc.subject.keywordPlus | PATIENT | - |
dc.subject.keywordPlus | AZD9291 | - |
dc.subject.keywordAuthor | Osimertinib | - |
dc.subject.keywordAuthor | NSCLC | - |
dc.subject.keywordAuthor | EGFR exon 20 insertion | - |
dc.subject.keywordAuthor | Resistance | - |
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