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Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors in Patients With De Novo EGFR(T790M)-Mutant NSCLC
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Park, Ha-Ram | - |
dc.contributor.author | Kim, Tae Min | - |
dc.contributor.author | Lee, Yusoo | - |
dc.contributor.author | Kim, Soyeon | - |
dc.contributor.author | Park, Seongyeol | - |
dc.contributor.author | Ju, Young Seok | - |
dc.contributor.author | Kim, Miso | - |
dc.contributor.author | Keam, Bhumsuk | - |
dc.contributor.author | Jeon, Yoon Kyung | - |
dc.contributor.author | Kim, Dong-Wan | - |
dc.contributor.author | Heo, Dae Seog | - |
dc.date.accessioned | 2022-04-20T10:27:48Z | - |
dc.date.available | 2022-04-20T10:27:48Z | - |
dc.date.created | 2021-11-25 | - |
dc.date.created | 2021-11-25 | - |
dc.date.issued | 2021-11 | - |
dc.identifier.citation | Journal of Thoracic Oncology, Vol.16 No.11, pp.1859-1871 | - |
dc.identifier.issn | 1556-0864 | - |
dc.identifier.other | 148424 | - |
dc.identifier.uri | https://hdl.handle.net/10371/179089 | - |
dc.description.abstract | Introduction: EGFRT790M mostly exists subclonally and is acquired as the most common mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs). Nevertheless, because de novo EGFRT790M-mutant NSCLC is rare, little is known on acquired resistance mechanisms to third -generation EGFR TKIs. Methods: Acquired resistance mechanisms were analyzed using tumor and plasma samples before and after third-generation EGFR TKI treatment in four patients with de novo EGFRT790M-mutant NSCLC. Genetic alterations were analyzed by whole-exome sequencing, targeted sequencing, fluorescence in situ hybridization, and droplet digital PCR. MTORL1433S, confirmed for oncogenicity using the Ba/F3 system, was reproduced in H1975 cell lines using CRISPR/ Cas9-RNP. Results: Of seven patients with NSCLC with de novo EGFRT790M/L858R mutation, four (LC1-4) who received third-generation EGFR TKIs acquired resistance after achieving a partial response (median 1/4 27 mo, range: 17-48 mo). Novel MTORL1433S and EGFRC797S/L798I mu-tations in cis, MET amplification, and EGFRC797S mutation were identified as acquired resistance mechanisms to third-generation EGFR TKIs. The MTORL1433S mutation was oncogenic in Ba/F3 models and revealed resistance to osimertinib through AKT signaling activation in NCI-H19 75 cells harboring the MTORL1433S mutation edited by CRISPR/Cas9 (half-maximal inhibitory con-centration, 800 +/- 67 nM). Osimertinib in combination with mTOR inhibitors abrogated acquired resistance to osimertinib. Conclusions: Activation of bypass pathways and the EGFRC797S or EGFRC797S/L798I mutation were identified as acquired resistance mechanisms to third-generation EGFR TKIs in patients with NSCLC with de novo EGFRT790M mu-tation. In addition, MTORL1433S-and EGFRL858R/T790M-mutant NSCLC cells were sensitive to osimertinib plus mTOR inhibitors. (c) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. | - |
dc.language | 영어 | - |
dc.publisher | Elsevier Inc. | - |
dc.title | Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors in Patients With De Novo EGFR(T790M)-Mutant NSCLC | - |
dc.type | Article | - |
dc.contributor.AlternativeAuthor | 전윤경 | - |
dc.contributor.AlternativeAuthor | 김대형 | - |
dc.contributor.AlternativeAuthor | 허대석 | - |
dc.identifier.doi | 10.1016/j.jtho.2021.06.013 | - |
dc.citation.journaltitle | Journal of Thoracic Oncology | - |
dc.identifier.wosid | 000712467200013 | - |
dc.identifier.scopusid | 2-s2.0-85111392084 | - |
dc.citation.endpage | 1871 | - |
dc.citation.number | 11 | - |
dc.citation.startpage | 1859 | - |
dc.citation.volume | 16 | - |
dc.identifier.sci | 000712467200013 | - |
dc.description.isOpenAccess | N | - |
dc.contributor.affiliatedAuthor | Jeon, Yoon Kyung | - |
dc.contributor.affiliatedAuthor | Kim, Dong-Wan | - |
dc.contributor.affiliatedAuthor | Heo, Dae Seog | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.subject.keywordPlus | CELL LUNG-CANCER | - |
dc.subject.keywordPlus | GROWTH-FACTOR RECEPTOR | - |
dc.subject.keywordPlus | MTOR MUTATIONS | - |
dc.subject.keywordPlus | T790M | - |
dc.subject.keywordPlus | MECHANISMS | - |
dc.subject.keywordPlus | AZD9291 | - |
dc.subject.keywordPlus | HETEROGENEITY | - |
dc.subject.keywordPlus | OSIMERTINIB | - |
dc.subject.keywordPlus | SENSITIVITY | - |
dc.subject.keywordPlus | EVOLUTION | - |
dc.subject.keywordAuthor | NSCLC | - |
dc.subject.keywordAuthor | De novo EGFR(T790M )mutation | - |
dc.subject.keywordAuthor | Third-generation EGFR TKIs | - |
dc.subject.keywordAuthor | Acquired resistance | - |
dc.subject.keywordAuthor | MTOR mutation | - |
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