RARG variant predictive of doxorubicin-induced cardiotoxicity identifies a cardioprotective therapy

Tarek Magdy, Zhengxin Jiang, Mariam Jouni, Hananeh Fonoudi, Davi Lyra-Leite, Gwanghyun Jung, Marisol Romero-Tejeda, Hui Hsuan Kuo, K. Ashley Fetterman, Mennat Gharib, Brian T. Burmeister, Mingming Zhao, Yadav Sapkota, Colin J. Ross, Bruce C. Carleton, Daniel Bernstein*, Paul W. Burridge

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2076-2089.e7
JournalCell stem cell
Volume28
Issue number12
DOIs
StatePublished - Dec 2 2021

Keywords

  • anthracycline
  • cardiomyocyte
  • cardiomyopathy
  • cardioprotection
  • cardiotoxocity
  • chemotherapy
  • doxorubicin
  • human induced pluripiotent stem cell
  • pharmacogenomics
  • variant

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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