# CX-5461 and doxorubicin activate a shared DNA damage-associated transcriptional response in human cardiomyocytes

## TL;DR

CX-5461, a cancer drug, causes DNA damage in heart cells similar to doxorubicin, suggesting potential cardiotoxicity.

## Contribution

The study identifies a shared DNA damage response in cardiomyocytes between CX-5461 and doxorubicin.

## Key findings

- CX-5461 induces cell death in cardiomyocytes at micromolar concentrations.
- CX activates DNA damage response pathways similar to those of doxorubicin.
- CX affects heart-specific genes and genes linked to doxorubicin cardiotoxicity.

## Abstract

CX-5461 (CX) is under investigation for the treatment of late-stage cancers. While CX was first described as an RNA polymerase I inhibitor, it has recently been shown to primarily inhibit the beta isoform of topoisomerase II. This isoform is also inhibited by anthracycline drugs including doxorubicin (DOX) and mediates the toxic effects of these drugs on the heart. It is unclear whether CX will similarly cause cardiotoxicity. We therefore tested the effects of CX on iPSC-derived cardiomyocytes from 6 individuals. CX induces cell death in cardiomyocytes at micromolar concentrations. Transcriptome profiling following treatment over time reveals gene expression programs that correspond to the DNA damage response, which are pathways shared with DOX response genes. Micromolar CX concentrations affect heart-specific genes and 14 functionally validated genes in loci associated with DOX cardiotoxicity. Our data demonstrate the impact of CX on the transcriptome of cardiomyocytes, a potential off-target cell type of the drug.