CYP2D6 loss of heterozygosity - a potential target for neuroblastoma therapy

Loss of heterozygosity events, whereby alleles are lost at heterozygous chromosomal loci, are associated with cancer formation and may result in the deletion of numerous genes encoding enzymes that have critical activities within the cell. Consequently, vulnerabilities are created that are absent in normal cells which can be targeted using a precision medicine approach called collateral lethality. A recent bioinformatic analysis of genomic variants identified LOH of CYP2D6 as a potential target for neuroblastoma therapy based on the prevalence of LOH occurrence and probability of a loss of function allele at this locus. Neuroblastoma cell lines with unmodified CYP2D6 function and models with enhanced function were screened with a small set of anti-cancer drugs that may be metabolized by CYP2D6. Despite low CYP2D6 expression levels in neuroblastoma cells in comparison to healthy liver tissue, four hits were identified that showed greater potency in tumour cells with low CYP2D6 activity. This study can be used as a framework for evaluating other LOH targets in various cancer types.