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

doi:10.1016/j.stem.2021.08.006

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

Pharmacology

Research output: Contribution to journal › Article › peer-review

47 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 language	English (US)
Pages (from-to)	2076-2089.e7
Journal	Cell stem cell
Volume	28
Issue number	12
DOIs	https://doi.org/10.1016/j.stem.2021.08.006
State	Published - Dec 2 2021

Funding

This work was supported by NIH grants K99/R00 HL121177 , R01 CA220002 , and R01 CA261898 ; American Heart Association Transformational Project Award 18TPA34230105 ; and Leducq Foundation 19CVD02 (to P.W.B.); the Canadian Cancer Society (to C.J.R., B.C.C., and P.W.B.); Michael Smith Foundation for Health Research Scholar Award (to C.J.R.); and NIH R33 HL123655 (to D.B. and B.C.C.). Patients from which hiPSCs were derived were recruited by the Canadian Pharmacogenomics Network for Drug Safety (by B.C.C. and C.J.R.), which has received grant funding from the Canadian Institutes for Health Research (CIHR), the CIHR Drug Safety and Effectiveness Network , Genome Canada , Genome British Columbia , and the British Columbia Provincial Health Services Authority .

Keywords

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

ASJC Scopus subject areas

Genetics
Molecular Medicine
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.stem.2021.08.006

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Magdy, T., Jiang, Z., Jouni, M., Fonoudi, H., Lyra-Leite, D., Jung, G., Romero-Tejeda, M., Kuo, H. H., Fetterman, K. A., Gharib, M., Burmeister, B. T., Zhao, M., Sapkota, Y., Ross, C. J., Carleton, B. C., Bernstein, D., & Burridge, P. W. (2021). RARG variant predictive of doxorubicin-induced cardiotoxicity identifies a cardioprotective therapy. Cell stem cell, 28(12), 2076-2089.e7. https://doi.org/10.1016/j.stem.2021.08.006

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title = "RARG variant predictive of doxorubicin-induced cardiotoxicity identifies a cardioprotective therapy",

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",

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

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year = "2021",

month = dec,

day = "2",

doi = "10.1016/j.stem.2021.08.006",

language = "English (US)",

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Magdy, T, Jiang, Z, Jouni, M, Fonoudi, H, Lyra-Leite, D, Jung, G, Romero-Tejeda, M, Kuo, HH, Fetterman, KA, Gharib, M, Burmeister, BT, Zhao, M, Sapkota, Y, Ross, CJ, Carleton, BC, Bernstein, D & Burridge, PW 2021, 'RARG variant predictive of doxorubicin-induced cardiotoxicity identifies a cardioprotective therapy', Cell stem cell, vol. 28, no. 12, pp. 2076-2089.e7. https://doi.org/10.1016/j.stem.2021.08.006

TY - JOUR

T1 - RARG variant predictive of doxorubicin-induced cardiotoxicity identifies a cardioprotective therapy

AU - Magdy, Tarek

AU - Jiang, Zhengxin

AU - Jouni, Mariam

AU - Fonoudi, Hananeh

AU - Lyra-Leite, Davi

AU - Jung, Gwanghyun

AU - Romero-Tejeda, Marisol

AU - Kuo, Hui Hsuan

AU - Fetterman, K. Ashley

AU - Gharib, Mennat

AU - Burmeister, Brian T.

AU - Zhao, Mingming

AU - Sapkota, Yadav

AU - Ross, Colin J.

AU - Carleton, Bruce C.

AU - Bernstein, Daniel

AU - Burridge, Paul W.

PY - 2021/12/2

Y1 - 2021/12/2

N2 - 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.

AB - 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.

KW - anthracycline

KW - cardiomyocyte

KW - cardiomyopathy

KW - cardioprotection

KW - cardiotoxocity

KW - chemotherapy

KW - doxorubicin

KW - human induced pluripiotent stem cell

KW - pharmacogenomics

KW - variant

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DO - 10.1016/j.stem.2021.08.006

M3 - Article

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AN - SCOPUS:85115138989

SN - 1934-5909

VL - 28

SP - 2076-2089.e7

JO - Cell stem cell

JF - Cell stem cell

IS - 12

ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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