CYP2D6的杂合性丧失增强肝细胞癌对塔拉唑帕比的敏感性

Loss of heterozygosity of CYP2D6 enhances the sensitivity of hepatocellular carcinomas to talazoparib

EBioMedicine

影响因子:10.8

分区:医学1区 Top / 医学：研究与实验1区

发表日期:2024 Nov

作者: Xiaonan Zhang, Natallia Rameika, Lei Zhong, Verónica Rendo, Margus Veanes, Snehangshu Kundu, Sandro Nuciforo, Jordan Dupuis, Muhammad Al Azhar, Ioanna Tsiara, Pauline Seeburger, Shahed Al Nassralla, Viktor Ljungström, Richard Svensson, Ivaylo Stoimenov, Per Artursson, Markus H Heim, Daniel Globisch, Tobias Sjöblom

DOI: 10.1016/j.ebiom.2024.105368

摘要

杂合性丧失（LOH）减少了癌症基因组的遗传多样性。在具有功能等位基因和功能缺失（LoF）等位基因的个体中，出现的肿瘤偶尔仅保留LoF等位基因。这可能导致癌细胞中特定蛋白质活性的缺失，从而在肿瘤细胞与个体正常细胞之间形成独特差异。这些差异可能成为利用等位基因特异性疗法的漏洞。为了发现常见的LoF等位基因频繁丧失的基因，我们分析了1000基因组数据集中通过碱基取代、插入缺失或剪接位点破坏导致蛋白质截短的单核苷酸变异（SNV），共识别出60个LoF变异在60个基因中。选择了其中位于多个肿瘤类型（包括肝细胞癌）常发生LOH的基因CYP2D6的变异rs3892097。为了评估CYP2D6活性与抗癌药物毒性的关系，我们利用含有或不含CYP2D6活性的细胞模型系统筛选了525种目前临床使用或正在临床试验的化合物。我们发现了12种化合物，即AZD-3463、CYC-116、依托泊苷、依维莫司、GDC-0349、雷帕替尼、MK-8776、PHA-680632、塔拉唑帕比、酪氨酸激酶抑制剂9、VX-702和WZ-3146，使用工程化的HEK293T细胞模型进行筛选。在这些中，塔拉唑帕比和MK-8776在CYP2D6活性受损的肝细胞癌细胞模型中表现出持续增强的细胞毒性作用。此外，塔拉唑帕比在原发性肝细胞癌类器官中表现出依赖CYP2D6基因型的效应。利用肿瘤细胞中药物代谢酶基因活性的丧失作为靶向癌症治疗的潜在策略具有前景。本研究由Barncancerfonden（T.S，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 Persson Foundation（T.S，2020-0037和T.S，2023-0113）资助。

Abstract

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).