• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

EZH2 和 ATM 抑制联合治疗 BAP1 缺陷性间皮瘤。

Combination of EZH2 and ATM inhibition in BAP1-deficient mesothelioma.

机构信息

Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands.

Oncode Institute, Jaarbeursplein 6, Utrecht, The Netherlands.

出版信息

Br J Cancer. 2024 May;130(11):1855-1865. doi: 10.1038/s41416-024-02661-3. Epub 2024 Mar 22.

DOI:10.1038/s41416-024-02661-3
PMID:38519707
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11130181/
Abstract

BACKGROUND

More than half of mesothelioma tumours show alterations in the tumour suppressor gene BAP1. BAP1-deficient mesothelioma is shown to be sensitive to EZH2 inhibition in preclinical settings but only showed modest efficacy in clinical trial. Adding a second inhibitor could potentially elevate EZH2i treatment efficacy while preventing acquired resistance at the same time.

METHODS

A focused drug synergy screen consisting of 20 drugs was performed by combining EZH2 inhibition with a panel of anti-cancer compounds in mesothelioma cell lines. The compounds used are under preclinical investigation or already used in the clinic. The synergistic potential of the combinations was assessed by using the Bliss model. To validate our findings, in vivo xenograft experiments were performed.

RESULTS

Combining EZH2i with ATMi was found to have synergistic potential against BAP1-deficient mesothelioma in our drug screen, which was validated in clonogenicity assays. Tumour growth inhibition potential was significantly increased in BAP1-deficient xenografts. In addition, we observe lower ATM levels upon depletion of BAP1 and hypothesise that this might be mediated by E2F1.

CONCLUSIONS

We demonstrated the efficacy of the combination of ATM and EZH2 inhibition against BAP1-deficient mesothelioma in preclinical models, indicating the potential of this combination as a novel treatment modality using BAP1 as a biomarker.

摘要

背景

超过一半的间皮瘤肿瘤显示肿瘤抑制基因 BAP1 的改变。在临床前研究中，BAP1 缺陷型间皮瘤对 EZH2 抑制敏感，但在临床试验中仅显示出适度的疗效。同时抑制两种蛋白可能会提高 EZH2i 治疗的疗效，同时防止获得性耐药。

方法

通过将 EZH2 抑制与间皮瘤细胞系中的一组抗癌化合物组合，进行了一个由 20 种药物组成的药物协同作用筛选。所用的化合物正在进行临床前研究或已在临床使用。通过 Bliss 模型评估组合的协同潜力。为了验证我们的发现，进行了体内异种移植实验。

结果

在我们的药物筛选中，发现 EZH2i 与 ATMi 联合使用对 BAP1 缺陷型间皮瘤具有协同作用，这在集落形成实验中得到了验证。BAP1 缺陷型异种移植中的肿瘤生长抑制潜力显著增加。此外，我们观察到 BAP1 耗竭时 ATM 水平降低，我们假设这可能是由 E2F1 介导的。

结论

我们在临床前模型中证明了 ATM 和 EZH2 抑制联合使用对 BAP1 缺陷型间皮瘤的疗效，表明该联合治疗作为一种新的治疗方法具有潜力，将 BAP1 作为生物标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01d2/11130181/fb51ea81388c/41416_2024_2661_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01d2/11130181/e61115b2a790/41416_2024_2661_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01d2/11130181/11921ce41ed5/41416_2024_2661_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01d2/11130181/31997ae90a7a/41416_2024_2661_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01d2/11130181/7fcbf2f14ee2/41416_2024_2661_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01d2/11130181/fb51ea81388c/41416_2024_2661_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01d2/11130181/e61115b2a790/41416_2024_2661_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01d2/11130181/11921ce41ed5/41416_2024_2661_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01d2/11130181/31997ae90a7a/41416_2024_2661_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01d2/11130181/7fcbf2f14ee2/41416_2024_2661_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/01d2/11130181/fb51ea81388c/41416_2024_2661_Fig5_HTML.jpg

相似文献

1
Combination of EZH2 and ATM inhibition in BAP1-deficient mesothelioma.EZH2 和 ATM 抑制联合治疗 BAP1 缺陷性间皮瘤。
Br J Cancer. 2024 May;130(11):1855-1865. doi: 10.1038/s41416-024-02661-3. Epub 2024 Mar 22.
2
Combined Inhibition of EZH2 and FGFR is Synergistic in BAP1-deficient Malignant Mesothelioma.EZH2 和 FGFR 的联合抑制在 BAP1 缺陷性恶性间皮瘤中具有协同作用。
Cancer Res Commun. 2024 Jan 3;4(1):18-27. doi: 10.1158/2767-9764.CRC-23-0276.
3
Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma.遗传筛选揭示了 BAP1 缺陷性间皮瘤的新可靶向弱点。
Cell Rep Med. 2023 Feb 21;4(2):100915. doi: 10.1016/j.xcrm.2022.100915. Epub 2023 Jan 18.
4
Comprehensive Pharmacogenomic Profiling of Malignant Pleural Mesothelioma Identifies a Subgroup Sensitive to FGFR Inhibition.全面的恶性胸膜间皮瘤药物基因组分析确定了对 FGFR 抑制敏感的亚组。
Clin Cancer Res. 2018 Jan 1;24(1):84-94. doi: 10.1158/1078-0432.CCR-17-1172. Epub 2017 Oct 23.
5
Functional Genomic Screen in Mesothelioma Reveals that Loss of Function of BRCA1-Associated Protein 1 Induces Chemoresistance to Ribonucleotide Reductase Inhibition.间皮瘤中的功能基因组筛选表明，BRCA1相关蛋白1功能丧失会导致对核糖核苷酸还原酶抑制产生化学抗性。
Mol Cancer Ther. 2020 Feb;19(2):552-563. doi: 10.1158/1535-7163.MCT-19-0356. Epub 2019 Oct 16.
6
Highly expressed EZH2 in combination with BAP1 and MTAP loss, as detected by immunohistochemistry, is useful for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia.免疫组织化学检测到 EZH2 高表达，结合 BAP1 和 MTAP 缺失，有助于鉴别恶性胸膜间皮瘤与反应性间皮增生。
Lung Cancer. 2019 Apr;130:187-193. doi: 10.1016/j.lungcan.2019.02.004. Epub 2019 Feb 27.
7
Loss of BAP1 function leads to EZH2-dependent transformation.BAP1功能丧失导致EZH2依赖性转化。
Nat Med. 2015 Nov;21(11):1344-9. doi: 10.1038/nm.3947. Epub 2015 Oct 5.
8
Diagnostic utility of BAP1 and EZH2 expression in malignant mesothelioma.BAP1 和 EZH2 表达在恶性间皮瘤中的诊断效用。
Histopathology. 2017 Apr;70(5):722-733. doi: 10.1111/his.13123. Epub 2017 Jan 5.
9
Loss of the deubiquitylase BAP1 alters class I histone deacetylase expression and sensitivity of mesothelioma cells to HDAC inhibitors.去泛素化酶BAP1的缺失会改变I类组蛋白去乙酰化酶的表达以及间皮瘤细胞对HDAC抑制剂的敏感性。
Oncotarget. 2015 May 30;6(15):13757-71. doi: 10.18632/oncotarget.3765.
10
EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study.EZH2 抑制剂 tazemetostat 治疗复发性或难治性、BAP1 失活的恶性胸膜间皮瘤患者：一项多中心、开放标签、2 期研究。
Lancet Oncol. 2022 Jun;23(6):758-767. doi: 10.1016/S1470-2045(22)00277-7. Epub 2022 May 16.

引用本文的文献

1
[Recent Advances in Medical Treatment of Malignant Pleural Mesothelioma].[恶性胸膜间皮瘤的医学治疗新进展]
Zhongguo Fei Ai Za Zhi. 2025 May 20;28(5):391-399. doi: 10.3779/j.issn.1009-3419.2025.102.18.
2
BAP1 Mutations and Pleural Mesothelioma: Genetic Insights, Clinical Implications, and Therapeutic Perspectives.BAP1突变与胸膜间皮瘤：遗传学见解、临床意义及治疗前景
Cancers (Basel). 2025 May 6;17(9):1581. doi: 10.3390/cancers17091581.
3
ERS Congress 2024: highlights from the Thoracic Oncology Assembly.2024年欧洲呼吸学会大会：胸部肿瘤学大会亮点

本文引用的文献

1
Interplay between EZH2/β-catenin in stemness of cisplatin-resistant HNSCC and their role as therapeutic targets.EZH2/β-catenin 在顺铂耐药头颈部鳞状细胞癌干性中的相互作用及其作为治疗靶点的作用。
Cell Signal. 2023 Sep;109:110773. doi: 10.1016/j.cellsig.2023.110773. Epub 2023 Jun 16.
2
Study on the Effect of EZH2 Inhibitor Combined with TIGIT Monoclonal Antibody against Multiple Myeloma Cells.EZH2 抑制剂联合 TIGIT 单克隆抗体对多发性骨髓瘤细胞作用的研究。
Int J Mol Sci. 2023 May 11;24(10):8603. doi: 10.3390/ijms24108603.
3
Did the Ban on Asbestos Reduce the Incidence of Mesothelioma?
ERJ Open Res. 2025 Apr 22;11(2). doi: 10.1183/23120541.01171-2024. eCollection 2025 Mar.
4
An overview of BAP1 biological functions and current therapeutics.BAP1生物学功能及当前治疗方法概述。
Biochim Biophys Acta Rev Cancer. 2025 Apr;1880(2):189267. doi: 10.1016/j.bbcan.2025.189267. Epub 2025 Jan 21.
5
Getting the right combination to break the epigenetic code.找到正确的组合来破解表观遗传密码。
Nat Rev Clin Oncol. 2025 Feb;22(2):117-133. doi: 10.1038/s41571-024-00972-1. Epub 2024 Dec 2.
6
Targeted Therapy in Mesotheliomas: Uphill All the Way.间皮瘤的靶向治疗：一路艰难前行。
Cancers (Basel). 2024 May 22;16(11):1971. doi: 10.3390/cancers16111971.
石棉禁令是否降低了间皮瘤的发病率？
J Thorac Oncol. 2023 Jun;18(6):694-697. doi: 10.1016/j.jtho.2023.03.013.
4
Global Incidence, Risk Factors, and Temporal Trends of Mesothelioma: A Population-Based Study.全球间皮瘤的发病率、风险因素和时间趋势：一项基于人群的研究。
J Thorac Oncol. 2023 Jun;18(6):792-802. doi: 10.1016/j.jtho.2023.01.095. Epub 2023 Feb 10.
5
Genetic screens reveal new targetable vulnerabilities in BAP1-deficient mesothelioma.遗传筛选揭示了 BAP1 缺陷性间皮瘤的新可靶向弱点。
Cell Rep Med. 2023 Feb 21;4(2):100915. doi: 10.1016/j.xcrm.2022.100915. Epub 2023 Jan 18.
6
Rational combinations of targeted cancer therapies: background, advances and challenges.靶向癌症治疗的合理组合：背景、进展与挑战
Nat Rev Drug Discov. 2023 Mar;22(3):213-234. doi: 10.1038/s41573-022-00615-z. Epub 2022 Dec 12.
7
Combined inhibition of EZH2 and ATM is synthetic lethal in BRCA1-deficient breast cancer.EZH2 和 ATM 的联合抑制在 BRCA1 缺陷型乳腺癌中具有合成致死性。
Breast Cancer Res. 2022 Jun 17;24(1):41. doi: 10.1186/s13058-022-01534-y.
8
EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study.EZH2 抑制剂 tazemetostat 治疗复发性或难治性、BAP1 失活的恶性胸膜间皮瘤患者：一项多中心、开放标签、2 期研究。
Lancet Oncol. 2022 Jun;23(6):758-767. doi: 10.1016/S1470-2045(22)00277-7. Epub 2022 May 16.
9
Combined Inhibition of G9a and EZH2 Suppresses Tumor Growth via Synergistic Induction of IL24-Mediated Apoptosis.联合抑制 G9a 和 EZH2 通过协同诱导 IL24 介导的细胞凋亡抑制肿瘤生长。
Cancer Res. 2022 Apr 1;82(7):1208-1221. doi: 10.1158/0008-5472.CAN-21-2218.
10
First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743.一线纳武利尤单抗联合伊匹木单抗与化疗治疗不可切除恶性胸膜间皮瘤患者：CheckMate 743研究的3年结果
Ann Oncol. 2022 May;33(5):488-499. doi: 10.1016/j.annonc.2022.01.074. Epub 2022 Feb 3.