Academic Journal
Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors in Patients With De Novo EGFR(T790M)-Mutant NSCLC
| العنوان: | Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors in Patients With De Novo EGFR(T790M)-Mutant NSCLC |
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| المؤلفون: | Park, Ha-Ram, Kim, Tae Min, Lee, Yusoo, Kim, Soyeon, Park, Seongyeol, Ju, Young Seok, Kim, Miso, Keam, Bhumsuk, Jeon, Yoon Kyung, Kim, Dong-Wan, Heo, Dae Seog |
| المساهمون: | 전윤경, 김대형, 허대석, Kim, Dong-Wan |
| سنة النشر: | 2021 |
| المجموعة: | Seoul National University: S-Space |
| مصطلحات موضوعية: | NSCLC, De novo EGFR(T790M )mutation, Third-generation EGFR TKIs, Acquired resistance, MTOR mutation |
| الوصف: | 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. ; Y |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| تدمد: | 1556-0864 |
| Relation: | Journal of Thoracic Oncology, Vol.16 No.11, pp.1859-1871; 148424; https://hdl.handle.net/10371/179089; 2-s2.0-85111392084; https://www.sciencedirect.com/science/article/pii/S1556086421022541?via%3Dihub; 000712467200013 |
| DOI: | 10.1016/j.jtho.2021.06.013 |
| الاتاحة: | https://hdl.handle.net/10371/179089 https://doi.org/10.1016/j.jtho.2021.06.013 https://www.sciencedirect.com/science/article/pii/S1556086421022541?via%3Dihub |
| رقم الانضمام: | edsbas.37A429C3 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 15560864 |
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| DOI: | 10.1016/j.jtho.2021.06.013 |