Identification of drug transporter genomic variants and inhibitors that protect against doxorubicin-induced cardiotoxicity

The main aim of this study was to explore the genetic variants within the SLC28A3 gene and their role in protecting against doxorubicin-induced cardiotoxicity (DIC). Doxorubicin is a widely used anticancer drug, but its use is limited by its cardiotoxic effects. The study sought to identify genetic variants and inhibitors that could mitigate these adverse effects. Human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes were used to model patient-specific responses to doxorubicin, helping to identify protective genetic loci and drug candidates that can reduce cardiotoxicity without compromising the anticancer efficacy of doxorubicin.

Oxford Nanopore MinION sequencing was used for fine-mapping the SLC28A3 gene locus to uncover a novel cardioprotective single nucleotide polymorphism (SNP), rs11140490. This variant regulates the expression of an antisense long noncoding RNA, SLC28A3-AS1, which is linked to doxorubicin uptake in cardiomyocytes.

The major findings include the identification of rs11140490 as a causal variant that protects against DIC by regulating the expression of SLC28A3-AS1. Additionally, the study identified the drug desipramine, an inhibitor of the SLC transporter, as a potential cardioprotective agent. Desipramine was shown to reduce doxorubicin uptake in cardiomyocytes, thus protecting them from toxicity without diminishing the drug’s effectiveness in treating cancer. This study highlights the potential for personalized genetic testing to predict and mitigate the risk of DIC, alongside identifying new therapeutic strategies for cardioprotection during chemotherapy.