The cytotoxicity of gefitinib on patient‑derived induced pluripotent stem cells reflects gefitinib‑induced liver injury in the clinical setting

Fujisaka,Yasuhito; Nakagawa,Takatoshi; Tomoda,Kiichiro; Watanabe,Marina; Matsunaga,Ninso; Tamura,Yosuke; Ikeda,Soichiro; Imagawa,Akihisa; Asahi,Michio

doi:10.3892/ol.2023.14108

The cytotoxicity of gefitinib on patient‑derived induced pluripotent stem cells reflects gefitinib‑induced liver injury in the clinical setting

Authors:
- Yasuhito Fujisaka
- Takatoshi Nakagawa
- Kiichiro Tomoda
- Marina Watanabe
- Ninso Matsunaga
- Yosuke Tamura
- Soichiro Ikeda
- Akihisa Imagawa
- Michio Asahi
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Affiliations: Department of Medical Oncology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569‑0801, Japan, Department of Pharmacology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569‑0801, Japan, Department of Internal Medicine (I), Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569‑0801, Japan
Published online on: October 18, 2023 https://doi.org/10.3892/ol.2023.14108
Article Number: 520
Copyright: © Fujisaka et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Gefitinib is a key drug used in the treatment of non‑small cell lung cancer (NSCLC) with EGFR mutations. Gefitinib therapy is superior to conventional chemotherapy for the progression‑free survival rate of patients with EGFR mutations. However, 10‑26% of patients develop grade 3 or higher hepatotoxicity during gefitinib treatment; therefore, the development of preclinical tests for hepatotoxicity prior to clinical use is desirable. The present study evaluated the use of induced pluripotent stem cells (iPSCs) and iPSC‑derived hepatocytes (iPSC‑heps), as a platform for preclinical test development. Patient‑derived iPSCs were generated by reprogramming peripheral blood mononuclear cells obtained from two groups of gefitinib‑treated patients with severe hepatotoxicity [toxicity group (T group)] or mild hepatotoxicity [no clinical toxicity group (N group)]. To examine the hepatotoxicity, the iPSCs from both T and N groups were differentiated into hepatocytes to obtain iPSC‑heps. Differentiation was confirmed by measuring the expression levels of hepatocyte markers, such as albumin or α‑fetoprotein, via western blotting and quantitative PCR analyses. Cytotoxicity in iPSCs and iPSC‑heps after gefitinib treatment was evaluated using a lactate dehydrogenase release assay. The gefitinib‑induced cytotoxicity in iPSCs from the T group was significantly higher than that from the N group, whereas there were no significant differences between the groups of iPSC‑heps. These results suggested that using iPSCs in preclinical assessment may be a good indicator for the prediction of gefitinib‑induced cytotoxicity in clinical use.

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