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Updated: Oct 1, 2025
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Molecular landscape of osimertinib resistance in patients and patient-derived preclinical models
Sun Min Lim1, San-Duk Yang2, Sangbin Lim3
1Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
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.
Insights
Osimertinib resistance in non-small cell lung cancer (NSCLC) is often driven by EGFR C797S mutations. Combination therapies targeting resistance mutations show promise for overcoming osimertinib failure in NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) approved for EGFR-mutant non-small cell lung cancer (NSCLC).
- Acquired resistance to osimertinib limits its long-term efficacy in NSCLC patients.
- Understanding resistance mechanisms is crucial for developing effective treatment strategies.
Purpose of the Study:
- To investigate acquired resistance mechanisms in NSCLC patients treated with osimertinib.
- To identify genetic alterations driving osimertinib resistance using preclinical models.
- To explore potential therapeutic strategies to overcome osimertinib resistance.
Main Methods:
- Analysis of tumor and plasma samples from 55 NSCLC patients at baseline and progressive disease using next-generation sequencing (600-gene panel).
- Generation and whole exome/RNA sequencing of osimertinib-resistant cell lines and patient-derived xenografts (PDX).
- In vitro experiments to functionally validate acquired mutations and test combination therapies.
Main Results:
- EGFR C797S mutation was the most frequent EGFR-dependent resistance mechanism (14%) in progression samples.
- EGFR-independent resistance mechanisms included mutations in PIK3CA, ALK, BRAF, EP300, KRAS, and RAF1.
- Targetable mutations like NRAS p.Q61K and KRAS p.G12D were identified in resistant models, demonstrating sensitivity to combination therapies (osimertinib + trametinib, or osimertinib + trametinib + buparlisib).
Conclusions:
- Targeted deep sequencing of osimertinib-resistant NSCLC patient samples revealed key genetic profiles.
- In vitro and in vivo models identified novel treatment strategies for osimertinib failure.
- Combination therapies targeting identified resistance mutations represent promising therapeutic avenues.
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