CYP2D6的杂合性丧失增强了肝细胞癌对Talazoparib的敏感性
Loss of heterozygosity of CYP2D6 enhances the sensitivity of hepatocellular carcinomas to talazoparib
影响因子:10.80000
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
摘要
杂合性（LOH）的丧失会减少癌症基因组中的遗传多样性。基因的功能性和功能丧失（LOF）等位基因的单个杂合引起的肿瘤有时仅保留LOF等位基因。这可能导致癌细胞中特定蛋白质活性的缺乏，从而在肿瘤细胞和个体的正常细胞之间产生独特的差异。这种差异可能构成可以通过等位基因特异性疗法来利用的脆弱性。要发现经常具有普遍LOF等位基因的基因，我们挖掘了1000个基因组数据集用于SNVS，通过碱基替代，Indels或剪接位点中断引起蛋白质截断，导致60个LOF变种，导致60个基因中的60种LOF。从中，选择了肝酶CYP2D6中的变体RS3892097，因为它位于经常在包括肝细胞癌在内的几种肿瘤类型中经常经历LOH的基因组区域。为了评估CYP2D6活性与抗癌剂的毒性之间的关系，我们使用具有或没有CYP2D6活性的细胞模型系统筛选了目前在临床使用或正在进行临床试验中的525种化合物。我们确定了12种化合物，AZD-3463，azd-3463，cyc-116，cyc-116，cyc-116，cyc-116，eToposide，eToposide，everolimus，gdc-limus，gdc-0349，lenvat，lenvat，mk-len，lenvat，mn。 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在工程肝癌细胞模型中表现出对细胞的细胞毒性始终增强，CYP2D6活性受损。此外，Talazoparib在原发性肝细胞癌中显示了CYP2D6基因型依赖性作用。探索在杂合性丧失后，肿瘤细胞中药物代谢酶基因活性丧失的丧失，可以提出靶向癌症治疗的有希望的治疗策略。 PR2020-0171，X.Z，TJ2021-0111），Cancerfonden（T.S，211719PJ和D.G，222449PJ），Vetenskapsrådet（T.S，T.S，2020-02371和D.G，D.G，D.G，2020-04707），以及Erling Persson基金会（T.Sssson Foundation）（T.Sssson Fundats），2020-s，T.-20202020202020-003-003 2023-0113）。
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).