RARG variant predictive of doxorubicin-induced cardiotoxicity identifies a cardioprotective therapy
Autor: | Daniel Bernstein, Colin J. D. Ross, Yadav Sapkota, Mariam Jouni, Hananeh Fonoudi, Gwanghyun Jung, Marisol Romero-Tejeda, Mingming Zhao, Bruce Carleton, Mennat Gharib, Zhengxin Jiang, Davi M. Lyra-Leite, Hui Hsuan Kuo, Brian T. Burmeister, K. Ashley Fetterman, Tarek Magdy, Paul W. Burridge |
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Rok vydání: | 2021 |
Předmět: |
Agonist
MAPK/ERK pathway Anthracycline medicine.drug_class medicine.medical_treatment Induced Pluripotent Stem Cells Biology Article Mice Risk Factors Genetics medicine Animals Humans Doxorubicin Myocytes Cardiac Cardioprotection Cardiotoxicity Chemotherapy Antibiotics Antineoplastic Cell Biology Retinoic acid receptor Cancer research Molecular Medicine medicine.drug Genome-Wide Association Study |
Zdroj: | Cell Stem Cell |
ISSN: | 1875-9777 |
Popis: | Summary Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but its use is limited by dose-dependent cardiotoxicity. A recent genome-wide association study identified a SNP (rs2229774) in retinoic acid receptor-γ (RARG) as statistically associated with increased risk of anthracycline-induced cardiotoxicity. Here, we show that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with rs2229774 and who suffered doxorubicin-induced cardiotoxicity (DIC) are more sensitive to doxorubicin. We determine that the mechanism of this RARG variant effect is mediated via suppression of topoisomerase 2β (TOP2B) expression and activation of the cardioprotective extracellular regulated kinase (ERK) pathway. We use patient-specific hiPSC-CMs as a drug discovery platform, determining that the RARG agonist CD1530 attenuates DIC, and we confirm this cardioprotective effect in an established in vivo mouse model of DIC. This study provides a rationale for clinical prechemotherapy genetic screening for rs2229774 and a foundation for the clinical use of RARG agonist treatment to protect cancer patients from DIC. |
Databáze: | OpenAIRE |
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