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Molecular landscape of osimertinib resistance in patients and patient-derived preclinical models

Authors
 Sun Min Lim  ;  San-Duk Yang  ;  Sangbin Lim  ;  Seong Gu Heo  ;  Stetson Daniel  ;  Aleksandra Markovets  ;  Rafati Minoo  ;  Kyoung-Ho Pyo  ;  Mi Ran Yun  ;  Min Hee Hong  ;  Hye Ryun Kim  ;  Byoung Chul Cho 
Citation
 THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY, Vol.14, 2022-02 
Journal Title
THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY
ISSN
 1758-8340 
Issue Date
2022-02
Keywords
EGFR inhibitor ; drug resistance ; lung cancer ; non-small cell lung cancer ; targeted therapy
Abstract
Introduction: Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) that is approved for the use of EGFR-mutant non-small cell lung cancer (NSCLC) patients. In this study, we investigated the acquired resistance mechanisms in NSCLC patients and patient-derived preclinical models.

Methods: Formalin-fixed paraffin-embedded tumor samples and plasma samples from 55 NSCLC patients who were treated with osimertinib were collected at baseline and at progressive disease (PD). Next-generation sequencing was performed in tumor and plasma samples using a 600-gene hybrid capture panel designed by AstraZeneca. Osimertinib-resistant cell lines and patient-derived xenografts and cells were generated and whole exome sequencing and RNA sequencing were performed. In vitro experiments were performed to functionally study the acquired mutations identified.

Results: A total of 55 patients and a total of 149 samples (57 tumor samples and 92 plasma samples) were analyzed, and among them 36 patients had matched pre- and post-treatment samples. EGFR C797S (14%) mutation was the most frequent EGFR-dependent mechanism identified in all available progression samples, followed by EGFR G824D (6%), V726M (3%), and V843I (3%). Matched pre- and post-treatment sample analysis revealed in-depth acquired mechanisms of resistance. EGFR C797S was still most frequent (11%) among EGFR-dependent mechanism, while among EGFR-independent mechanisms, PIK3CA, ALK, BRAF, EP300, KRAS, and RAF1 mutations were detected. Among Osimertinib-resistant cell lines and patient-derived models, we noted acquired mutations which were potentially targetable such as NRAS p.Q61K, in which resistance could be overcome with combination of osimertinib and trametinib. A patient-derived xenograft established from osimertinib-resistant patient revealed KRAS p.G12D mutation which could be overcome with combination of osimertinib, trametinib, and buparlisib.

Conclusion: In this study, we explored the genetic profiles of osimertinib-resistant NSCLC patient samples using targeted deep sequencing. In vitro and in vivo models harboring osimertinib resistance revealed potential novel treatment strategies after osimertinib failure.
Files in This Item:
T202203034.pdf Download
DOI
10.1177/17588359221079125
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Yun, Mi Ran(윤미란)
Lim, Sun Min(임선민)
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
Pyo, Kyoung Ho(표경호) ORCID logo https://orcid.org/0000-0001-5428-0288
Heo, Seong Gu(허성구)
Hong, Min Hee(홍민희) ORCID logo https://orcid.org/0000-0003-3490-2195
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/189586
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