Anthracyclines induce cardiotoxicity through a shared gene expression response signature

Area of Science:

• Cardiology
• Genomics
• Pharmacology

Background:

• Topoisomerase II inhibitors (TOP2i) are vital breast cancer drugs but can cause cardiotoxicity.
• The cardiotoxic effects of specific TOP2i, including anthracyclines (AC) like Doxorubicin (DOX), are not fully understood.
• Individual responses to TOP2i vary, suggesting a genetic component to cardiotoxicity risk.

Purpose of the Study:

• To investigate the cardiotoxic effects of various TOP2i on human cardiomyocytes.
• To identify shared and distinct gene expression changes induced by TOP2i.
• To explore the role of genetic variations in inter-individual responses to TOP2i cardiotoxicity.

Main Methods:

• Treatment of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from six healthy females with DOX, Daunorubicin (DNR), Epirubicin (EPI), Mitoxantrone (MTX), and Trastuzumab (TRZ).
• Assessment of cell death, cellular stress, and calcium handling.
• Analysis of genome-wide gene expression changes and identification of response signatures.
• Integration of expression quantitative trait loci (eQTLs) and genome-wide/transcriptome-wide association studies (GWAS/TWAS) data.

Main Results:

• All tested TOP2i induced cell death at clinically relevant concentrations and affected cardiomyocyte calcium handling at sub-lethal doses.
• TOP2i triggered thousands of shared gene expression changes, categorized into early-acute, early-sustained, and late response signatures, with no drug- or AC-specific patterns.
• Genes near single nucleotide polymorphisms (SNPs) associated with DOX response and AC cardiotoxicity were enriched in TOP2i-responsive genes, indicating a genetic influence on variable responses.

Conclusions:

• TOP2i induce common molecular responses in cardiomyocytes, contributing to cardiotoxicity.
• Individual genetic variations influence the response to TOP2i, explaining inter-individual differences in cardiotoxicity.
• Understanding these shared pathways and genetic factors could inform personalized strategies to mitigate TOP2i-induced heart damage in cancer patients.