Cardiotoxicity Assessment of EGFR Tyrosine Kinase Inhibitors Using Human iPS Cell-Derived Cardiomyocytes and FDA Adverse Events Reporting System.

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Cardiotoxicity Assessment of EGFR Tyrosine Kinase Inhibitors Using Human iPS Cell-Derived Cardiomyocytes and FDA Adverse Events Reporting System.

Cardiotoxicity Assessment of EGFR Tyrosine Kinase Inhibitors Using Human iPS Cell-Derived Cardiomyocytes and FDA Adverse Events Reporting System.

アブストラクト	Recent advances in the development of anti-cancer drugs have contributed to prolonged survival of cancer patients. In contrast, drug-induced cardiotoxicity, particularly cardiac contractile dysfunction, is of growing concern in cancer treatment. Therefore, it is important to understand the risks of anti-cancer drug-induced cardiac contractile dysfunction in drug development. We have previously developed image-based motion analysis using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to assess the effect of drugs on contractility. However, the utility and predictive potential of image-based motion analysis using hiPSC-CMs for anti-cancer drug-induced cardiac contractile dysfunction have not been well understood. Here we focused on epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) and investigated the correlation between the hiPSC-CMs data and clinical signals of adverse events related to cardiac contractile dysfunction. We examined the effects of the four EGFR-TKIs, osimertinib, gefitinib, afatinib, and erlotinib, on the contractility of hiPSC-CMs using image-based motion analysis. We found that osimertinib decreased contraction velocity and deformation distance in a dose- and time-dependent manner, whereas gefitinib, afatinib, and erlotinib had little effect on these parameters. Next, we examined the real-world data of the EGFR-TKIs using FDA Adverse Event Reporting System (FAERS; JAPIC AERS). Only osimertinib showed significant clinical signals of adverse events related to cardiac contractile dysfunction. These data suggest that hiPSC-CM data correlate with clinical signals in FAERS analysis for four EGFR-TKIs. Thus, image-based motion analysis using hiPSC-CMs can be a useful platform for predicting the risk of anti-cancer drug-induced cardiac contractile dysfunction in patients.
ジャーナル名	Clinical and translational science
Pubmed追加日	2025/8/18
投稿者	Yanagida, Shota; Kawagishi, Hiroyuki; Saito, Mitsuo; Hamano, Hirofumi; Zamami, Yoshito; Kanda, Yasunari
組織名	Division of Pharmacology, National Institute of Health Sciences (NIHS), Kawasaki,;Kanagawa, Japan.;Japan Pharmaceutical Information Center (JAPIC), Tokyo, Japan.;Department of Pharmacy, Okayama University Hospital, Okayama, Japan.
Pubmed リンク	https://www.ncbi.nlm.nih.gov/pubmed/40820655/