期刊
CELL STEM CELL
卷 28, 期 12, 页码 2076-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2021.08.006
关键词
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资金
- NIH [R33 HL123655, K99/R00 HL121177, R01 CA220002, R01 CA261898]
- American Heart Association Transformational Project Award [18TPA34230105]
- Leducq Foundation [19CVD02]
- Canadian Cancer Society
- Michael Smith Foundation for Health Research Scholar Award
- Canadian Institutes for Health Research (CIHR)
- CIHR Drug Safety and Effectiveness Network
- Genome Canada
- Genome British Columbia
- British Columbia Provincial Health Services Authority
A recent study identified a genetic variant associated with anthracycline-induced cardiotoxicity and elucidated its mechanism using hiPSC-CMs. The study found that an RARG agonist can attenuate DIC, providing a new approach for clinical prechemotherapy genetic screening and treatment.
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-gamma (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 2 beta (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.
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