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

  • Cell Stem Cell. 2021 Dec 2;28(12):2076-2089.e7. doi: 10.1016/j.stem.2021.08.006.
Tarek Magdy  1 ,  Zhengxin Jiang  1 ,  Mariam Jouni  1 ,  Hananeh Fonoudi  1 ,  Davi Lyra-Leite  1 ,  Gwanghyun Jung  2 ,  Marisol Romero-Tejeda  1 ,  Hui-Hsuan Kuo  1 ,  K Ashley Fetterman  1 ,  Mennat Gharib  1 ,  Brian T Burmeister  1 ,  Mingming Zhao  2 ,  Yadav Sapkota  3 ,  Colin J Ross  4 ,  Bruce C Carleton  5 ,  Daniel Bernstein  6 ,  Paul W Burridge  7
Affiliations
  • 1. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 2. Department of Pediatrics (Division of Cardiology), Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 3. Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 4. British Columbia Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
  • 5. British Columbia Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada; Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, BC V6T 1Z2, Canada; Pharmaceutical Outcomes Programme, British Columbia Children's Hospital, Vancouver, BC V5Z 4H4, Canada.
  • 6. Department of Pediatrics (Division of Cardiology), Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].
  • 7. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: [email protected].
PMID: 34525346 DOI: 10.1016/j.stem.2021.08.006
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.

Keywords
anthracycline; cardiomyocyte; cardiomyopathy; cardioprotection; cardiotoxocity; chemotherapy; doxorubicin; human induced pluripiotent stem cell; pharmacogenomics; variant.
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