Related Experiment Video
Updated: Nov 3, 2025
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma
Seok-Young Kim1, Sang-Min Kim2, Sumin Lim3
1Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
Purpose:
Patient-derived organoids (PDO) of lung cancer has been recently introduced, reflecting the genomic landscape of lung cancer. However, clinical relevance of advanced lung adenocarcinoma organoids remains unknown. Here, we examined the ability of PDOs to predict clinical responses to targeted therapies in individual patients and to identify effective anticancer therapies for novel molecular targets.
Experimental Design:
Eighty-four organoids were established from patients with advanced lung adenocarcinoma. Formalin-fixed, paraffin-embedded tumor specimens from corresponding patients were analyzed by whole-exome sequencing (n = 12). Organoids were analyzed by whole-exome sequencing (n = 61) and RNA sequencing (n = 55). Responses to mono or combination targeted therapies were examined in organoids and organoid-derived xenografts.
Results:
PDOs largely retained somatic alterations including driver mutations of matching patient tumors. PDOs were able to recapitulate progression-free survival and objective responses of patients with non-small cell lung cancer receiving clinically approved tyrosine kinase inhibitors. PDOs recapitulated activity of therapeutic strategies under clinical investigation. YUO-071 harboring an EGFR exon 19 deletion and a BRAF G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an EGFR L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to identify effective therapies for novel molecular targets by demonstrating the efficacy of poziotinib against ERBB2 exon 20 insertions and pralsetinib against RET fusions.
Conclusions:
We demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool, which can assist clinical decision making and accelerate development of therapeutic strategies.
Insights
Patient-derived organoids (PDOs) accurately predict lung cancer patient responses to targeted therapies. These organoids are valuable tools for personalized medicine and accelerating the development of new lung adenocarcinoma treatments.
Area of Science:
- Oncology
- Genomics
- Translational Medicine
Background:
- Patient-derived organoids (PDOs) are emerging models reflecting lung cancer's genomic complexity.
- The clinical utility of advanced lung adenocarcinoma PDOs in predicting treatment outcomes remains largely unestablished.
Purpose of the Study:
- To assess the predictive capability of lung adenocarcinoma PDOs for individual patient responses to targeted therapies.
- To identify effective anticancer therapies for novel molecular targets using PDO models.
Main Methods:
- Established 84 organoids from advanced lung adenocarcinoma patients.
- Performed whole-exome sequencing on tumor specimens (n=12) and organoids (n=61).
- Conducted RNA sequencing on organoids (n=55) and evaluated responses to targeted therapies in organoids and derived xenografts.
Main Results:
- PDOs largely preserved somatic alterations and driver mutations from patient tumors.
- PDOs successfully recapitulated patient responses to tyrosine kinase inhibitors and clinical trial therapies.
- Demonstrated efficacy of poziotinib for ERBB2 insertions and pralsetinib for RET fusions in PDO models.
Conclusions:
- Validated the translational relevance of PDOs for advanced lung adenocarcinoma.
- Highlighted PDOs as crucial diagnostic tools for clinical decision-making and therapeutic strategy development.
