Loss of CYP2D6 sensitizes hepatocellular carcinomas and neuroblastomas to talazoparib

Abstract Cancers often have reduced allelic diversity because of loss of heterozygosity (LOH). Therefore, tumors arising in patients heterozygous for a functional and a loss-of-functon(LoF) allele may lose the functional allele, rendering them sensitive to allele-specific therapies. To discover such alleles, we mined the 1000 Genomes dataset for SNVs causing protein truncation through base substitution, indels or splice site disruptions, resulting in 60 LoF variants in 60 genes. The LoF splice site variant rs3892097 in CYP2D6 was selected as it resides in a genomic region undergoing LOH in different tumor types, is highly polymorphic with over 135 allelic variants, and metabolizes ~25% of clinically used drugs. We generated cell systems and screened anticancer agents in clinical use or in clinical trials for differential toxicity, and Talazoparib and MK-8776 were shown to exhibit consistent cytotoxicity against hepatocellular carcinoma and MYCN-amplified neuroblastoma cells with low CYP2D6 activity in 2D and 3D culture. Moreover, Talazoparib displayed CYP2D6 genotype dependent effects on primary hepatocellular carcinoma organoids. These findings support a new therapeutic strategy targeting LoF variants of drug-metabolizing enzymes, enabling anticancer drug selection for precision medicine.