Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma
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Abstract
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.
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PDO retain the morphological and characteristics of human primary tumors.
“PDO have become an effective clinical-related model for predicting the drug responses, and they retain the morphological and characteristics of human primary tumors (38–40).”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [40]
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Self-citationScientific Validation and Clinical Application of Lung Cancer Organoids
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Cell Culture Model Evolution and Its Impact on Improving Therapy Efficiency in Lung Cancer
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Organoids in lung cancer: A teenager with infinite growth potential
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Patient-derived organoids as a model for tumor research
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Lung cancer organoids: models for preclinical research and precision medicine
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Organoid drug profiling identifies methotrexate as a therapy for SCCOHT, a rare pediatric cancer
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Self-citationPreclinical models for development of immune–oncology therapies
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Open questions in human lung organoid research
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A systematic review of patient-derived tumor organoids generation from malignant effusions
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Exploring tumor organoids for cancer treatment
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Preclinical Models for Functional Precision Lung Cancer Research
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Female Reproductive Tract Organoids: Applications from Physiology to Pathology
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Bridging the gap: how patient-derived lung cancer organoids are transforming personalized medicine
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Establishment of Human Lung Cancer Organoids Using Small Biopsy and Surgical Tissues
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Self-citationOrganoid-based precision cancer modeling: New frontier in lung cancer research
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Applied models and molecular characteristics of small cell lung cancer
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Recent advances in lung cancer organoid (tumoroid) research (Review)
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Organoid for Air Pollution Toxicity Assessment: Advances and Environmental Applicability
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Anticipating EGFR Targeting in Early Stages of Lung Cancer: Leave No Stone Unturned
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Patient-derived organoids in non-small cell lung cancer: advances in drug sensitivity testing
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Review on Advanced Cancer Modeling for a Cancer Study
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Self-citationApplications and perspectives of tumor organoids in radiobiology (Review)
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Self-citationSelection of the Most Suitable Culture Medium for Patient-Derived Lung Cancer Organoids
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Patient-Derived Organoids as a Stem Cell Model to Study Lung Cancer
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Tumor Immune Engineering: Developing In Vitro Assays to Understand the Tumor–Immune Crosstalk
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Approaches to modeling cancer metastasis: from bench to bedside
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Deconstructing cancer in 3D: models, mechanisms, and personalized solutions
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Brain metastasis organoids: A systematic review of their methods and clinical application
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- Authors
- Kim, S.-Y., Kim, S.-M., Lim, S., Lee, J. Y., Choi, S.-J., Yang, S.-D., Yun, M. R., Kim, C. G., Gu, S. R., Park, C., Park, A.-Y., Lim, S. M., Heo, S. G., Kim, H., & Cho, B. C.
- Affiliations
- Yonsei University (KR)
- 3Interpark Bio Convergence Corp., Seoul, Korea.
- Corresponding author
- Heo, Seong Gu
- Kim, HyunKi
- Cho, Byoung Chul
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2021-06-03
- Volume
- 27
- Issue
- 15
- Pages
- 4397-4409
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC9401503
- OpenAlex
- W3164073476
- Cited by
- 151
- References
- 56
- Citations by year
- 2026: 26 · 2025: 35 · 2024: 39 · 2023: 28 · 2022: 19 · 2021: 4
- FWCI
- 14.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Clinical Cancer Research (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Interpark bio Convergence
- Ministry of Science and ICT, South Korea (2016R1A2B3016282)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- patient-derived organoids, advanced lung adenocarcinoma, non-small cell lung cancer, targeted therapy response prediction, tyrosine kinase inhibitors, dabrafenib/trametinib, EGFR exon 19 deletion, afatinib, poziotinib, pralsetinib, RET fusion, translational oncology
- MeSH terms
- Adenocarcinoma of Lung, Antineoplastic Agents, Humans, Lung Neoplasms, Models, Biological, Neoplasm Staging, Organoids
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