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Updated: Mar 6, 2026
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Personalized pharmacokinetic-pharmacodynamic guided therapy via an induced pluripotent stem cell-derived
Jung Hwa Lim1,2, Seon Ju Mun3, Hyun Mi Kang1,2
1Disease modeling and therapeutics team, Stem cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
Abstract:
Effective precision oncology demands integration of pharmacokinetics/pharmacodynamics (PK/PD) profiling with tumor-specific genomic features. Here, we present a personalized treatment model using a patient-derived Networking Organoid Culture System (NOCS) composed of intestinal, liver, and kidney organoids differentiated from induced pluripotent stem cells (iPSCs) of an NF1-mutant breast cancer patient. This multi-organoid system enabled individualized assessment of drug absorption, distribution, metabolism, and excretion. Integrative genomic and pathway analyses uncovered therapeutic vulnerabilities, including responsiveness to a novel exon skipping therapy targeting NF1. PK/PD-guided screening on the NOCS prioritized Paxalisib, which, when combined with the exon skipping approach, demonstrated synergistic anticancer efficacy in patient-derived tumor models. These findings establish a clinically relevant framework that integrates multi-organ PK/PD modeling with genotype-driven therapeutic strategies, highlighting the potential of combining targeted gene correction with small-molecule therapy for personalized treatment. This platform offers broad applicability in precision oncology and drug development across diverse genetic contexts.
Insights
This study developed a personalized organoid model for NF1-mutant breast cancer, integrating pharmacokinetics/pharmacodynamics (PK/PD) with genomics. The model identified a combination therapy of exon skipping and Paxalisib, showing synergistic anticancer effects.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Precision oncology requires integrating pharmacokinetics/pharmacodynamics (PK/PD) with tumor genomics.
- Patient-derived organoid models offer a platform for personalized drug testing.
Purpose of the Study:
- To develop and validate a personalized treatment model for NF1-mutant breast cancer.
- To integrate multi-organ PK/PD profiling with genomic data for therapeutic strategy development.
Main Methods:
- Established a Networking Organoid Culture System (NOCS) using patient-derived induced pluripotent stem cells (iPSCs).
- Performed individualized PK/PD assessments (absorption, distribution, metabolism, excretion).
- Conducted integrative genomic and pathway analyses to identify therapeutic vulnerabilities.
Main Results:
- The NOCS enabled comprehensive PK/PD evaluation and identified NF1 exon skipping therapy responsiveness.
- PK/PD-guided screening prioritized Paxalisib, demonstrating synergistic efficacy with exon skipping in patient models.
- The integrated approach successfully combined gene correction with small-molecule therapy.
Conclusions:
- This framework integrates multi-organ PK/PD modeling with genotype-driven strategies for personalized oncology.
- The NOCS platform shows broad applicability for precision oncology and drug development in diverse genetic contexts.
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