Acquired Resistance to Third-Generation EGFR Tyrosine Kinase Inhibitors in Patients With De Novo EGFR(T790M)-Mutant NSCLC

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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.
Publisher
ELSEVIER SCIENCE INC
Issue Date
2021-11
Language
English
Article Type
Article
Citation

JOURNAL OF THORACIC ONCOLOGY, v.16, no.11, pp.1859 - 1871

ISSN
1556-0864
DOI
10.1016/j.jtho.2021.06.013
URI
http://hdl.handle.net/10203/289364
Appears in Collection
MSE-Journal Papers(저널논문)
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