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Molecular landscape of osimertinib resistance in patients and patient-derived preclinical models
| Content Provider | SAGE Publishing |
|---|---|
| Author | Lim, Sun Min Yang, San-Duk Lim, Sangbin Heo, Seong Gu Daniel, Stetson Markovets, Aleksandra Minoo, Rafati Pyo, Kyoung-Ho Yun, Mi Ran Hong, Min Hee Kim, Hye Ryun Cho, Byoung Chul |
| Copyright Year | 2022 |
| 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. |
| Related Links | https://journals.sagepub.com/doi/pdf/10.1177/17588359221079125?download=true |
| ISSN | 17588359 |
| Volume Number | 14 |
| Journal | Therapeutic Advances in Medical Oncology (TAM) |
| e-ISSN | 17588359 |
| DOI | 10.1177/17588359221079125 |
| Language | English |
| Publisher | Sage Publications UK |
| Publisher Date | 2022-02-26 |
| Publisher Place | London |
| Access Restriction | Open |
| Rights Holder | © The Author(s), 2022 |
| Subject Keyword | non-small cell lung cancer drug resistance EGFR inhibitor lung cancer targeted therapy |
| Content Type | Text |
| Resource Type | Article |
| Subject | Oncology |
