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CRISPR screening using Human PSC-derived cardiomyocytes reveals TAOK1 as a potential therapeutic target for doxorubicin-induced cardiomyopathy I

ABSTRACT: Doxorubicin (DOX) is one of the most effective chemotherapeutic agents for various types of cancers. However, DOX often causes cardiotoxicity referred to as DOX-induced cardiomyopathy (DIC). Despite extensive research aimed at identifying therapeutic targets for DIC, only a limited number of effective treatments are available. In this study, we identified a member of the STE20 kinase family, thousand and one amino acid protein kinase 1 (TAOK1) as a potential regulator for DOX-induced cardiomyocyte death using a kinome-wide CRISPR gene knockout screen in human cardiomyocytes derived from pluripotent stem cells (hPSC-CMs). TAOK1 suppression improved DOX-induced cardiomyocyte dysfunction in hPSC-CMs and rescued cardiac function in a DIC mouse model. Mechanistically, we found that TAOK1 regulated p38 MAPK-mediated cardiomyocyte apoptosis induced by DOX. Our results indicate TAOK1 as a promising therapeutic strategy for treating DIC in cancer patients, and highlight the advantage of hPSC-CMs as a platform to study drug-induced cardiotoxicity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE255504 | GEO | 2026/02/08

REPOSITORIES: GEO

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Project description: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 anti-cancer treatments. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carry donor-specific genetic information and have been proposed for explore the inter-individual difference in oncology drug-induced cardiotoxicity. Herein, we evaluated the inter- and intra- individual variability of iPSC-CM-related assays and presented a practical approach for using donor-specific iPSC-CMs to predict personalized doxorubicin (DOX)-induced cardiotoxicity (DIC) prior to chemotherapy. Our findings demonstrated that donor-specific iPSC-CMs exhibited greater line-to-line variability than the intra-individual 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 of DIC. By categorizing iPSC-CMs into DOX-resistant and DOX-sensitive cell lines based on their phenotypic reactions to DOX, we found that the sensitivity of donor-specific iPSC-CMs to DOX may predict in vivo DIC risk. Furthermore, we assessed the limitations of the model for identification of potential genetic/molecular biomarker and pinpointed a differentially expressed gene, DND microRNA-mediated repression inhibitor 1 (DND1), between the DOX-resistant and DOX-sensitive iPSC-CMs. We also discussed the selection of DOX dose and exposure duration for inter-individual variability of DIC assessment. Our results support the utility of donor-specific iPSC-CMs in assessing inter-individual difference and enabling personalized cardiotoxicity prediction. Further studies will encompass a large panel of donor-specific iPSC-CMs to investigate the role of the DND1 and known DIC genetic variants, and to identify potential novel molecular and genetic biomarkers for predicting DOX and other oncology drug-induced cardiotoxicity.

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CRISPR screening using Human PSC-derived cardiomyocytes reveals TAOK1 as a potential therapeutic target for doxorubicin-induced cardiomyopathy I

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