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Publication

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

Cell stem cell | 2021

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.

Pubmed ID: 34525346 RIS Download

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Associated grants

Agency: NCI NIH HHS, United States
Id: R01 CA220002
Agency: NCI NIH HHS, United States
Id: R01 CA261898
Agency: CIHR, Canada
Agency: NHLBI NIH HHS, United States
Id: K99 HL121177
Agency: NCATS NIH HHS, United States
Id: TL1 TR001423
Agency: NHLBI NIH HHS, United States
Id: R33 HL123655
Agency: NHLBI NIH HHS, United States
Id: R00 HL121177

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Subread (tool)

RRID:SCR_009803

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DESeq2 (tool)

RRID:SCR_015687

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RRID:SCR_018982

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