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Progressive suppression of DNA repair genes with persistent p53 activation in Doxorubicin-treated cardiomyocytes

ABSTRACT: Doxorubicin (DOX) is an effective anti-cancer drug; however it can cause cardiotoxicity by inducing DNA double strand breaks in cardiomyocytes. Cardiotoxicity can present immediately or years following treatment. Most human in vitro models of DOX-induced cardiotoxicity (DIC) focus on the acute effects of DOX treatment. To understand the long-term effects, we profiled the global gene expression response to DOX exposure over time. We treated iPSC-derived cardiomyocytes from six individuals with DOX for 24 hours and assayed responses after 0, 24 and 144 hours of recovery. DNA damage, determined by γH2AX expression, is induced following DOX treatment and is resolved by the last recovery timepoint. We identified both acute and chronic gene expression response signatures. The chronic signature, representing 501 genes, is enriched for p53 target genes and DNA damage response genes compared to acute response genes. P53 target genes are persistently activated, and DNA damage response genes are progressively downregulated over time. Our results suggest an altered cell state following repair of double strand breaks that is distinct from pre-exposed cells. DOX response genes with persistent changes in expression can be applied to the design of toxicity biomarkers or therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313746 | GEO | 2026/05/26

REPOSITORIES: GEO

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Project description:TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. There is no drug- or AC-specific signature. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified 38 genes in loci associated with AC toxicity by GWAS or TWAS. Two thirds of the genes that respond to at least one TOP2i, respond to all ACs with the same direction of effect. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.

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Progressive suppression of DNA repair genes with persistent p53 activation in Doxorubicin-treated cardiomyocytes

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