CX-5461 induces cell death in human cardiomyocytes at micromolar concentrations, activating a DNA damage response similar to Doxorubicin's effects.
CX-5461, an investigational cancer drug, induces cell death and DNA damage-associated transcriptional responses in human cardiomyocytes similar to doxorubicin, suggesting potential off-target cardiotoxicity.
Absolute Event Rate: 0% vs 0%
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 six 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.
Paul et al. (Fri,) reported a other. CX-5461 induces cell death in human cardiomyocytes at micromolar concentrations, activating a DNA damage response similar to Doxorubicin's effects.