杂合性丢失 (LOH) 会减少癌症基因组内的遗传多样性。基因的功能等位基因和功能丧失 (LoF) 等位基因的杂合个体中产生的肿瘤有时仅保留 LoF 等位基因。这可能导致癌细胞中特定蛋白质活性的缺乏，从而在个体的肿瘤细胞和正常细胞之间产生独特的差异。这些差异可能构成可通过等位基因特异性疗法加以利用的漏洞。为了发现常见 LoF 等位基因中经常丢​​失的基因，我们挖掘了 1000 个基因组数据集中的 SNV，这些 SNV 通过碱基替换、插入缺失或剪接位点破坏导致蛋白质截断，从而导致 60 个 LoF 60个基因的变异。从这些中，选择了肝酶 CYP2D6 中的变体 rs3892097，因为它位于在包括肝细胞癌在内的多种肿瘤类型中经常发生 LOH 的基因组区域内。为了评估 CYP2D6 活性与抗癌药物毒性之间的关系，我们使用具有或不具有 CYP2D6 活性的细胞模型系统筛选了目前临床使用或正在进行临床试验的 525 种化合物。我们鉴定了 12 种化合物，AZD-3463、CYC-116、依托泊苷、依维莫司、GDC-0349、lenvatinib、MK-8776、PHA-680632、talazoparib、tyrphostin 9、VX-702 和 WZ-3146，使用工程 HEK293T 细胞模型。其中，talazoparib 和 MK-8776 在工程化肝细胞癌细胞模型中对 CYP2D6 活性受损的细胞表现出持续增强的细胞毒性作用。此外，talazoparib 对原发性肝细胞癌类器官表现出 CYP2D6 基因型依赖性效应。利用杂合性丢失后肿瘤细胞中药物代谢酶基因活性的丧失可能为靶向癌症治疗提供一种有前途的治疗策略。这项工作由 Barncancerfonden (T.S) 资助、PR2022-0099 和 PR2020-0171、X.Z、TJ2021-0111)、Cancerfonden (T.S, 211719Pj 和 D.G, 222449Pj)、Vetenskapsrådet (T.S, 2020-02371 和 D.G, 2020-04707) 以及 Erling Pers儿子基金会（T.S， 2020-0037 和 T.S，2023-0113)。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Loss of heterozygosity (LOH) diminishes genetic diversity within cancer genomes. A tumour arising in an individual heterozygous for a functional and a loss-of-function (LoF) allele of a gene occasionally retain only the LoF allele. This can result in deficiency of specific protein activities in cancer cells, creating unique differences between tumour cells and normal cells of the individual. Such differences may constitute vulnerabilities that can be exploited through 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. From these, the variant rs3892097 in the liver enzyme CYP2D6 was selected because it is located within a genomic region that frequently undergoes LOH in several tumor types including hepatocellular cancers. To evaluate the relationship between CYP2D6 activity and the toxicities of anticancer agents, we screened 525 compounds currently in clinical use or undergoing clinical trials using cell model systems with or without CYP2D6 activity.We identified 12 compounds, AZD-3463, CYC-116, etoposide, everolimus, GDC-0349, lenvatinib, MK-8776, PHA-680632, talazoparib, tyrphostin 9, VX-702, and WZ-3146, using an engineered HEK293T cell model. Of these, talazoparib and MK-8776 demonstrated consistently heightened cytotoxic effects against cells with compromised CYP2D6 activity in engineered hepatocellular cancer cell models. Moreover, talazoparib displayed CYP2D6 genotype dependent effects on primary hepatocellular carcinoma organoids.Exploiting the loss of drug-metabolizing enzyme gene activity in tumor cells following loss of heterozygosity could present a promising therapeutic strategy for targeted cancer treatment.This work was funded by Barncancerfonden (T.S, PR2022-0099 and PR2020-0171, X.Z, TJ2021-0111), Cancerfonden (T.S, 211719Pj and D.G, 222449Pj), Vetenskapsrådet (T.S, 2020-02371 and D.G, 2020-04707), and the Erling Persson Foundation (T.S, 2020-0037 and T.S, 2023-0113).Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.