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Optimizing drug sensitivity assays in patient-derived tumor organoids: a comparison of IC50 estimation methods and
Yidan Chen1, Jian Zhang2, Bin Zhang3
1Hangzhou Cancer Institute, Hangzhou Cancer Hospital, Hangzhou, Zhejiang 310002, China.
Abstract:
Patient-derived tumor organoids (PDOs) hold immense potential for personalized drug sensitivity testing, but accurate efficacy determination is crucial for clinical translation. This study investigated factors influencing the accuracy and reproducibility of drug sensitivity measurements in PDOs, focusing on half-maximal-inhibitory-concentration (IC50) calculation methods, drug concentration numbers, and plate types. PDOs were established from six primary cancer tissues, including two cervical resections, one lung biopsy, one lung pleural effusion, one breast biopsy, and one gastric resection. They were subjected to drug sensitivity assays with 21 single/combined treatments, encompassing chemotherapy and targeted therapy drugs, with concentrations standardized in fold. Utilizing 6- and 12-concentration setups, IC50 derived from GraphPad-Dose-response-Inhibition (DRI), LC-logit, and LC-probit methods were compared. Relative changes (RCs) in IC50 and area-under-the dose-response-curve (AUC) between setups and the impact of plate type on cell viability measurements were assessed. In the 12-concentration setup, no significant IC50 differences were observed among the calculation methods. Notably, GraphPad-DRI and LC-logit exhibited minimal RCs between the 6- and 12-concentration setups (0.035 and -0.033, respectively), indicating accurate IC50 quantification even with fewer drug concentrations. AUC correlated strongly with GraphPad-DRI-derived IC50 (R = 0.858) and demonstrated lower variance between technical replicates. Furthermore, opaque-bottom plates yielded higher precision in cell viability measurements compared to transparent-bottom plates. This study provides valuable insights into optimizing drug sensitivity testing in PDOs. By demonstrating the robustness of specific IC50 calculation methods and the feasibility of using fewer drug concentrations, this study contributed to the standardization and reliability of PDO-based drug sensitivity assays.
Insights
Accurate drug sensitivity testing using patient-derived tumor organoids (PDOs) is achievable with optimized methods. Specific half-maximal-inhibitory-concentration (IC50) calculation methods and opaque plates enhance reliability for personalized cancer therapy.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Patient-derived tumor organoids (PDOs) show promise for personalized drug sensitivity testing.
- Accurate efficacy determination in PDOs is critical for clinical translation.
- Standardization of drug sensitivity assays in PDOs is needed.
Purpose of the Study:
- To investigate factors influencing accuracy and reproducibility of drug sensitivity measurements in PDOs.
- To compare half-maximal-inhibitory-concentration (IC50) calculation methods, drug concentration numbers, and plate types.
- To optimize PDO-based drug sensitivity assays for clinical application.
Main Methods:
- Established PDOs from six primary cancer tissues (cervical, lung, breast, gastric).
- Performed drug sensitivity assays with 21 treatments using 6- and 12-concentration setups.
- Compared IC50 values derived from GraphPad-Dose-response-Inhibition (DRI), LC-logit, and LC-probit methods; assessed area-under-the curve (AUC) and plate type impact.
Main Results:
- No significant IC50 differences observed among calculation methods in the 12-concentration setup.
- GraphPad-DRI and LC-logit showed minimal relative changes in IC50 between 6- and 12-concentration setups.
- Opaque-bottom plates provided higher precision in cell viability measurements compared to transparent-bottom plates.
Conclusions:
- Specific IC50 calculation methods (GraphPad-DRI, LC-logit) are robust for PDO drug sensitivity testing.
- Accurate IC50 quantification is feasible with fewer drug concentrations, aiding assay standardization.
- Optimized methods, including opaque plates, enhance the reliability of PDO-based drug sensitivity assays for personalized medicine.
