Elucidating Molecular Mechanisms of the Hepatotoxicity associated with Targeted Cancer Therapies

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07179
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Osaka Medical and Pharmaceutical University
• Principal Investigator: Fujisaka Yasuhito 大阪医科薬科大学, 医学部, 特別職務担当教員(教授) (50411369)
• Co-Investigator(Kenkyū-buntansha): 朝日 通雄 大阪医科薬科大学, 医学部, 教授 (10397614) ; 友田 紀一郎 大阪医科薬科大学, 医学部, 非常勤講師 (50362843)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ゲフィチニブ / 肝障害 / iPS細胞 / 肝細胞分化

Outline of Final Research Achievements

The purpose of this study was to establish an assay system predicting liver injury by gefitinib used in the treatment of non-small cell lung cancer. Patient-derived iPSCs (PD-iPSCs) were generated by reprogramming peripheral blood mononuclear cells (PBMCs) obtained from two groups of gefitinib-treated patients with moderate hepatotoxicity (H group) or no hepatotoxicity (N group). PD-iPSCs were partly differentiated into hepatocytes (PD-iPS-heps).Cytotoxicity in PD-iPSCs and PD-iPS-heps after gefitinib treatment was evaluated using a lactate dehydrogenase (LDH) release assay. The gefitinib-induced cytotoxicity in PD-iPSCs from the H group was significantly higher than those from the N group, whereas there were no significant differences between the groups in PD-iPS-heps. These results suggest that using PD-iPSCs in preclinical assessment may be a good indicator for the prediction of gefitinib-induced cytotoxicity in clinical use.

Free Research Field

臨床腫瘍学

Academic Significance and Societal Importance of the Research Achievements

ゲフィチニブは非小細胞性肺がんの主要な治療薬であるが、たとえ奏効していたとしても、肝障害により約10％の患者で治療の中断や多剤への変更を余儀なくされているのが現状である。本研究では、治療前の患者サンプルから作製したiPS細胞を用いてゲフィチニブによる細胞障害アッセイを行うことにより、事前に肝障害を予知でき、治療薬選択に役立てることができる可能性を示唆しており、ゲフィチニブの投与が最適治療であると考えられるがん患者には有用であると思われる。