Validating the pharmacogenomics of chemotherapy-induced cardiotoxicity: What is missing?

Abstract

The cardiotoxicity of certain chemotherapeutic agents is now well-established, and has led to the development of the field of cardio-oncology, increased cardiac screening of cancer patients, and limitation of patients' maximum cumulative chemotherapeutic dose. The effect of chemotherapeutic regimes on the heart largely involves cardiomyocyte death, leading to cardiomyopathy and heart failure, or the induction of arrhythmias. Of these cardiotoxic drugs, those resulting in clinical cardiotoxicity can range from 8 to 26% for doxorubicin, 7-28% for trastuzumab, or 5-30% for paclitaxel. For tyrosine kinase inhibitors, QT prolongation and arrhythmia, ischemia and hypertension have been reported in 2-35% of patients. Furthermore, newly introduced chemotherapeutic agents are commonly used as part of changed combinational regimens with significantly increased incidence of cardiotoxicity. It is widely believed that the mechanism of action of these drugs is often independent of their cardiotoxicity, and the basis for why these drugs specifically affect the heart has yet to be established. The genetic rationale for why certain patients experience cardiotoxicity whilst other patients can tolerate high chemotherapy doses has proven highly illusive. This has led to significant genomic efforts using targeted and genome-wide association studies (GWAS) to divine the pharmacogenomic cause of this predilection. With the advent of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), the putative risk and protective role of single nucleotide polymorphisms (SNPs) can now be validated in a human model. Here we review the state of the art knowledge of the genetic predilection to chemotherapy-induced cardiotoxicity and discuss the future for establishing and validating the role of the genome in this disease.

Keywords: Chemotherapy-induced cardiotoxicity; cardiomyopathy; human induced pluripotent stem cells; pharmacogenomics.

Figure 1. FDA-approved pharmacogenomics biomarker in drug labeling

Bar plot diagram showing number of drugs that contain pharmacogenetic testing information in their package insert, and their distribution across different therapeutic areas (n = 158)

Figure 2. Classification of genes harboring SNPs associated with DOX clinical outcome by class

Pie chart diagram showing the distribution of SNPs associated with DOX clinical outcome across different gene families.

Figure 3. Global minor allele frequency distribution of DOX genetic polymorphisms

Diagram showing global minor allele frequency (GMAF) of SNPs significantly associated with DOX clinical outcome, which demonstrates that individuals SNPs have significantly different allelic frequency in diverse populations. GMAF was adapted according to 1000 genomes project data base. This analysis was done using R/Bioconductor package biomaRt (Durinck et al., 2009).

Figure 4. Schematic diagram showing the multiple mechanisms of doxorubicin-induced cardiotoxicity

Genes associated with DOX clinical outcome are written in blue. Blue boxes show assays which identified a differentiation response between patients who had cardiotoxicity (DOXTOX) and patients who did not have toxicity (DOX) (Burridge et al., 2016), highlighting the fact that DOX related cardiotoxicity is a polygenic trait and thus, the comprehensive approach proposed in this project is needed to identify genetic biomarkers for DOX-induced cardiotoxicity. Doxorubicin (DOX), doxorubinol (DOX-ol), doxoerubicin-semiquinone (DOX-semiquinone), C7 centered radical aglycone (C7 radical), nitric oxide synthase 3 (NOS3), NADH dehydrogenases (collectively NAD(P)H oxidoreductases), P450 (cytochrome) oxidoreductase (POR), xanthine oxidase (XDH) superoxide radical (O₂-•), hydrogen peroxide (H₂O₂), hydroxyl radical (OH•), nitric oxide (NO•), peroxynitrite (ONOO-), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxide (GSH), glutathione disulfide (GSSG), peroxiredoxin (PRDX), myoglobin (MB), ferrous iron (Fe²⁺), ferric iron (Fe³⁺), dexrazoxane (DRZ), N-acetyl-L-cysteine (NAC), topoisomerase (DNA) 1 mitochondrial (TOP1MT), BCL2-associated X protein (BAX), cytochrome C (CYCS) tumor protein p53 (TP53), topoisomerase 2B (TOP2B), ryanodine receptor 2 (RYR2), ATPase, Ca²⁺ transporting, cardiac muscle slow twitch 2 (ATP2A2), myosin light chain (MYL), cardiac troponin T (TNNT), α-actinin (ACTA). Image modified from Burridge et al., 2016, used with permission.

Figure 5

Schematic of the process for elucidating the role of genetic mutations in chemotherapy-induced cardiotoxicity