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

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. Overall design: To gain insight into the mechanism underlying the protective effect of the TAOK1 knockout on DOX-induced cardiomyocyte death and dysfunction, we performed global gene expression analysis using RNA-seq in TAOK1- and Ctrl-KO hPSC-CMs treated with DOX.