%0 Journal Article
%T Predicting oncology drug-induced cardiotoxicity with donor-specific iPSC-CMs-a proof-of-concept study with doxorubicin.
%A Pang L
%A Cai C
%A Aggarwal P
%A Wang D
%A Vijay V
%A Bagam P
%A Blamer J
%A Matter A
%A Turner A
%A Ren L
%A Papineau K
%A Srinivasasainagendra V
%A Tiwari HK
%A Yang X
%A Schnackenberg L
%A Mattes W
%A Broeckel U
%J Toxicol Sci
%V 200
%N 1
%D 2024 Jun 26
%M 38547396
%F 4.109
%R 10.1093/toxsci/kfae041
%X Many oncology drugs have been found to induce cardiotoxicity in a subset of patients, which significantly limits their clinical use and impedes the benefit of lifesaving anticancer treatments. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carry donor-specific genetic information and have been proposed for exploring the interindividual difference in oncology drug-induced cardiotoxicity. Herein, we evaluated the inter- and intraindividual variability of iPSC-CM-related assays and presented a proof of concept to prospectively predict doxorubicin (DOX)-induced cardiotoxicity (DIC) using donor-specific iPSC-CMs. Our findings demonstrated that donor-specific iPSC-CMs exhibited greater line-to-line variability than the intraindividual variability in impedance cytotoxicity and transcriptome assays. The variable and dose-dependent cytotoxic responses of iPSC-CMs resembled those observed in clinical practice and largely replicated the reported mechanisms. By categorizing iPSC-CMs into resistant and sensitive cell lines based on their time- and concentration-related phenotypic responses to DOX, we found that the sensitivity of donor-specific iPSC-CMs to DOX may predict in vivo DIC risk. Furthermore, we identified a differentially expressed gene, DND microRNA-mediated repression inhibitor 1 (DND1), between the DOX-resistant and DOX-sensitive iPSC-CMs. Our results support the utilization of donor-specific iPSC-CMs in assessing interindividual differences in DIC. Further studies will encompass a large panel of donor-specific iPSC-CMs to identify potential novel molecular and genetic biomarkers for predicting DOX and other oncology drug-induced cardiotoxicity.