Loss of CYP2D6 sensitizes hepatocellular carcinomas to talazoparib

Loss of heterozygosity (LOH) results in decreased genetic diversity in cancer genomes. As a result, tumor cells in patients who carry a functional and a loss-of-function (LoF) allele of a gene may retain only the LoF allele after LOH. This reduction in heterozygosity can potentially make cancer cells susceptible to allele-specific therapies. To discover frequently lost genes with prevalent LoF 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 variant rs3892097 in CYP2D6 was selected because it is located within a genomic region that frequently undergoes LOH in several tumor types, potentially leading to the retention of only the LoF allele after LOH. To assess the CYP2D6 activity dependency of their toxicities, we screened 525 anticancer agents in clinical use or undergoing clinical trials using three different cell model systems. Our results revealed that talazoparib and MK-8776 consistently exhibited greater cytotoxic effects against cancer cells with compromised CYP2D6 activity in 2D as well as 3D culture. Moreover, talazoparib displayed CYP2D6 genotype dependent effects on primary hepatocellular carcinoma organoids. These findings support a novel therapeutic approach targeting LoF variants in the context of LOH events involving a drug-metabolizing enzyme, enabling the selection of anticancer drugs for CYP2D6 variation-based precision medicine.