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

Area of Science:

• Cardiology
• Genetics
• Pharmacology

Background:

• Doxorubicin is a vital chemotherapy drug, but its use is limited by dose-dependent cardiotoxicity.
• A genome-wide association study linked the RARG SNP rs2229774 to increased risk of anthracycline-induced cardiotoxicity.

Purpose of the Study:

• To investigate the mechanism by which the RARG variant rs2229774 contributes to doxorubicin-induced cardiotoxicity (DIC).
• To evaluate the therapeutic potential of RARG agonists in preventing or mitigating DIC.

Main Methods:

• Utilized patient-derived induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the rs2229774 variant.
• Assessed doxorubicin sensitivity and molecular pathways (TOP2B, ERK) in hiPSC-CMs.
• Tested the RARG agonist CD1530 in hiPSC-CMs and an in vivo mouse model of DIC.

Main Results:

• hiPSC-CMs with the rs2229774 variant exhibited heightened sensitivity to doxorubicin.
• The RARG variant's effect was mediated by suppressed TOP2B expression and activated ERK signaling.
• CD1530 treatment attenuated doxorubicin-induced cardiotoxicity in both cellular and animal models.

Conclusions:

• The RARG variant rs2229774 confers sensitivity to doxorubicin cardiotoxicity through specific molecular mechanisms.
• RARG agonists represent a promising therapeutic strategy to protect against chemotherapy-induced cardiotoxicity.
• Clinical genetic screening for rs2229774 and RARG agonist therapy warrant further investigation.