• 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

CDK7 抑制通过 MED1 失活抑制去势抵抗性前列腺癌。

CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation.

机构信息

Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

出版信息

Cancer Discov. 2019 Nov;9(11):1538-1555. doi: 10.1158/2159-8290.CD-19-0189. Epub 2019 Aug 29.

DOI:10.1158/2159-8290.CD-19-0189
PMID:31466944
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7202356/
Abstract

Metastatic castration-resistant prostate cancer (CRPC) is a fatal disease, primarily resulting from the transcriptional addiction driven by androgen receptor (AR). First-line CRPC treatments typically target AR signaling, but are rapidly bypassed, resulting in only a modest survival benefit with antiandrogens. Therapeutic approaches that more effectively block the AR-transcriptional axis are urgently needed. Here, we investigated the molecular mechanism underlying the association between the transcriptional coactivator MED1 and AR as a vulnerability in AR-driven CRPC. MED1 undergoes CDK7-dependent phosphorylation at T1457 and physically engages AR at superenhancer sites, and is essential for AR-mediated transcription. In addition, a CDK7-specific inhibitor, THZ1, blunts AR-dependent neoplastic growth by blocking AR/MED1 corecruitment genome-wide, as well as reverses the hyperphosphorylated MED1-associated enzalutamide-resistant phenotype. , THZ1 induces tumor regression of AR-amplified human CRPC in a xenograft mouse model. Together, we demonstrate that CDK7 inhibition selectively targets MED1-mediated, AR-dependent oncogenic transcriptional amplification, thus representing a potential new approach for the treatment of CRPC. SIGNIFICANCE: Potent inhibition of AR signaling is critical to treat CRPC. This study uncovers a driver role for CDK7 in regulating AR-mediated transcription through phosphorylation of MED1, thus revealing a therapeutically targetable potential vulnerability in AR-addicted CRPC...

摘要

转移性去势抵抗性前列腺癌 (CRPC) 是一种致命疾病，主要由雄激素受体 (AR) 驱动的转录成瘾引起。一线 CRPC 治疗通常针对 AR 信号，但很快被绕过，导致抗雄激素治疗仅能带来适度的生存获益。迫切需要更有效地阻断 AR 转录轴的治疗方法。在这里，我们研究了转录共激活因子 MED1 与 AR 之间的关联的分子机制，作为 AR 驱动的 CRPC 中的一个脆弱性。MED1 在 T1457 处经历 CDK7 依赖性磷酸化，并在超级增强子位点与 AR 物理结合，是 AR 介导的转录所必需的。此外，一种 CDK7 特异性抑制剂 THZ1 通过阻断 AR/MED1 核心募集全基因组，以及逆转高磷酸化 MED1 相关的恩杂鲁胺耐药表型，削弱了 AR 依赖性肿瘤生长。THZ1 在异种移植小鼠模型中诱导 AR 扩增的人 CRPC 的肿瘤消退。总之，我们证明 CDK7 抑制选择性靶向 MED1 介导的、AR 依赖性的致癌转录扩增，因此代表了治疗 CRPC 的一种潜在新方法。意义：强效抑制 AR 信号对于治疗 CRPC 至关重要。本研究揭示了 CDK7 通过磷酸化 MED1 调节 AR 介导的转录的驱动作用，从而揭示了 AR 成瘾性 CRPC 中可治疗的潜在脆弱性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2935/7202356/86f3fc71e6c5/nihms-1538416-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2935/7202356/314ecac64605/nihms-1538416-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2935/7202356/adf95c8fc186/nihms-1538416-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2935/7202356/ce1b1ea1b704/nihms-1538416-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2935/7202356/9874cae7c925/nihms-1538416-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2935/7202356/63caf593a3c2/nihms-1538416-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2935/7202356/3a7acaf9fef5/nihms-1538416-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2935/7202356/86f3fc71e6c5/nihms-1538416-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2935/7202356/314ecac64605/nihms-1538416-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2935/7202356/adf95c8fc186/nihms-1538416-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2935/7202356/ce1b1ea1b704/nihms-1538416-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2935/7202356/9874cae7c925/nihms-1538416-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2935/7202356/63caf593a3c2/nihms-1538416-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2935/7202356/3a7acaf9fef5/nihms-1538416-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2935/7202356/86f3fc71e6c5/nihms-1538416-f0007.jpg

相似文献

1
CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation.CDK7 抑制通过 MED1 失活抑制去势抵抗性前列腺癌。
Cancer Discov. 2019 Nov;9(11):1538-1555. doi: 10.1158/2159-8290.CD-19-0189. Epub 2019 Aug 29.
2
Androgen Receptor Interaction with Mediator Complex Is Enhanced in Castration-Resistant Prostate Cancer by CDK7 Phosphorylation of MED1.雄激素受体与中介复合物的相互作用在去势抵抗性前列腺癌中通过 CDK7 对 MED1 的磷酸化作用得到增强。
Cancer Discov. 2019 Nov;9(11):1490-1492. doi: 10.1158/2159-8290.CD-19-1028.
3
MED1 mediates androgen receptor splice variant induced gene expression in the absence of ligand.MED1在缺乏配体的情况下介导雄激素受体剪接变体诱导的基因表达。
Oncotarget. 2015 Jan 1;6(1):288-304. doi: 10.18632/oncotarget.2672.
4
A natural molecule, urolithin A, downregulates androgen receptor activation and suppresses growth of prostate cancer.一种天然分子，尿石素 A，可以下调雄激素受体的激活并抑制前列腺癌的生长。
Mol Carcinog. 2018 Oct;57(10):1332-1341. doi: 10.1002/mc.22848. Epub 2018 Aug 1.
5
Castration-resistant prostate cancer cells are dependent on the high activity of CDK7.去势抵抗性前列腺癌细胞依赖于 CDK7 的高活性。
J Cancer Res Clin Oncol. 2023 Jul;149(8):5255-5263. doi: 10.1007/s00432-022-04475-3. Epub 2022 Nov 18.
6
Cotargeting Androgen Receptor Splice Variants and mTOR Signaling Pathway for the Treatment of Castration-Resistant Prostate Cancer.共靶向雄激素受体剪接变体和mTOR信号通路用于治疗去势抵抗性前列腺癌。
Clin Cancer Res. 2016 Jun 1;22(11):2744-54. doi: 10.1158/1078-0432.CCR-15-2119. Epub 2015 Dec 28.
7
Validation of histone deacetylase 3 as a therapeutic target in castration-resistant prostate cancer.组蛋白去乙酰化酶3作为去势抵抗性前列腺癌治疗靶点的验证
Prostate. 2018 Mar;78(4):266-277. doi: 10.1002/pros.23467. Epub 2017 Dec 15.
8
The CDK7 inhibitor CT7001 (Samuraciclib) targets proliferation pathways to inhibit advanced prostate cancer.CDK7 抑制剂 CT7001（沙库巴曲）针对增殖途径抑制晚期前列腺癌。
Br J Cancer. 2023 Jun;128(12):2326-2337. doi: 10.1038/s41416-023-02252-8. Epub 2023 Apr 19.
9
Targeting Androgen Receptor Activation Function-1 with EPI to Overcome Resistance Mechanisms in Castration-Resistant Prostate Cancer.使用EPI靶向雄激素受体激活功能-1以克服去势抵抗性前列腺癌中的耐药机制。
Clin Cancer Res. 2016 Sep 1;22(17):4466-77. doi: 10.1158/1078-0432.CCR-15-2901. Epub 2016 May 2.
10
Targeting the KIF4A/AR Axis to Reverse Endocrine Therapy Resistance in Castration-resistant Prostate Cancer.靶向 KIF4A/AR 轴逆转去势抵抗性前列腺癌的内分泌治疗耐药性。
Clin Cancer Res. 2020 Mar 15;26(6):1516-1528. doi: 10.1158/1078-0432.CCR-19-0396. Epub 2019 Dec 3.

引用本文的文献

1
The Mediator Complex: A Regulatory Hub for Transcriptional Activity of Nuclear Receptors.中介体复合物：核受体转录活性的调控枢纽
Cells. 2025 Aug 28;14(17):1335. doi: 10.3390/cells14171335.
2
Liquid chromatography-tandem mass spectrometry assay for the simultaneous determination of apalutamide and its active metabolite N-desmethyl apalutamide, and its application in real-world patients with castration-resistant prostate cancer.液相色谱-串联质谱法同时测定阿帕鲁胺及其活性代谢物N-去甲基阿帕鲁胺及其在去势抵抗性前列腺癌真实世界患者中的应用
Front Pharmacol. 2025 May 19;16:1510583. doi: 10.3389/fphar.2025.1510583. eCollection 2025.
3

本文引用的文献

1
Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer.发现 ARD-69 是一种高效的蛋白酶靶向嵌合体（PROTAC）降解剂，可用于治疗前列腺癌的雄激素受体（AR）。
J Med Chem. 2019 Jan 24;62(2):941-964. doi: 10.1021/acs.jmedchem.8b01631. Epub 2019 Jan 10.
2
Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains.转录因子通过其激活结构域的相分离能力激活基因。
Cell. 2018 Dec 13;175(7):1842-1855.e16. doi: 10.1016/j.cell.2018.10.042. Epub 2018 Nov 15.
3
Castration-Resistant Prostate Cancer Refractory to Second-Generation Androgen Receptor Axis-Targeted Agents: Opportunities and Challenges.
MUC1-C dependency in drug resistant HR+/HER2- breast cancer identifies a new target for antibody-drug conjugate treatment.
耐药性 HR+/HER2- 乳腺癌中 MUC1-C 的依赖性确定了抗体药物偶联物治疗的新靶点。
NPJ Breast Cancer. 2025 Apr 26;11(1):39. doi: 10.1038/s41523-025-00751-w.
4
BCAT2 binding to PCBP1 regulates the PI3K/AKT signaling pathway to inhibit autophagy-related apoptosis and ferroptosis in prostate cancer.BCAT2与PCBP1结合可调节PI3K/AKT信号通路，以抑制前列腺癌中自噬相关的细胞凋亡和铁死亡。
Cell Death Dis. 2025 Apr 24;16(1):337. doi: 10.1038/s41419-025-07559-3.
5
Acute BRCAness induction and AR pathway blockage through CDK12/7/9 degradation enhances PARP inhibitor sensitivity in prostate cancer.通过CDK12/7/9降解诱导急性BRCAness并阻断AR途径可增强前列腺癌对PARP抑制剂的敏感性。
Sci Adv. 2025 Apr 25;11(17):eadu0847. doi: 10.1126/sciadv.adu0847. Epub 2025 Apr 23.
6
Dynamic O-GlcNAcylation and phosphorylation attract and expel proteins from RNA polymerase II to regulate mRNA maturation.动态的O-连接N-乙酰葡糖胺化和磷酸化作用吸引并驱离RNA聚合酶II上的蛋白质，从而调控信使核糖核酸的成熟。
J Biomed Sci. 2025 Apr 4;32(1):39. doi: 10.1186/s12929-025-01135-9.
7
Terbinafine for prostate cancer: development of coated zein nanospheres for ameliorated pro-apoptosis in PC3 cells.用于前列腺癌的特比萘芬：制备用于改善PC3细胞促凋亡作用的玉米醇溶蛋白包衣纳米球
Nanomedicine (Lond). 2025 Apr;20(8):817-833. doi: 10.1080/17435889.2025.2481823. Epub 2025 Apr 2.
8
Cyclin-dependent kinases as mediators of aberrant transcription in prostate cancer.细胞周期蛋白依赖性激酶作为前列腺癌异常转录的介质
Transl Oncol. 2025 May;55:102378. doi: 10.1016/j.tranon.2025.102378. Epub 2025 Mar 30.
9
Cyclin-Dependent Kinase Inhibition in Prostate Cancer: Past, Present, and Future.前列腺癌中细胞周期蛋白依赖性激酶抑制：过去、现在与未来
Cancers (Basel). 2025 Feb 24;17(5):774. doi: 10.3390/cancers17050774.
10
Cyclin-dependent protein kinases and cell cycle regulation in biology and disease.细胞周期蛋白依赖性蛋白激酶与生物学和疾病中的细胞周期调控
Signal Transduct Target Ther. 2025 Jan 13;10(1):11. doi: 10.1038/s41392-024-02080-z.
对第二代雄激素受体轴靶向药物难治的去势抵抗性前列腺癌：机遇与挑战
Cancers (Basel). 2018 Sep 21;10(10):345. doi: 10.3390/cancers10100345.
4
Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses.将前列腺癌细胞 AR 异质性与不同的去势和恩杂鲁胺反应联系起来。
Nat Commun. 2018 Sep 6;9(1):3600. doi: 10.1038/s41467-018-06067-7.
5
Coactivator condensation at super-enhancers links phase separation and gene control.共激活因子在超级增强子上的凝聚将相分离和基因调控联系起来。
Science. 2018 Jul 27;361(6400). doi: 10.1126/science.aar3958. Epub 2018 Jun 21.
6
Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing.通过链接读取基因组测序揭示推动去势抵抗性前列腺癌的结构改变。
Cell. 2018 Jul 12;174(2):433-447.e19. doi: 10.1016/j.cell.2018.05.036. Epub 2018 Jun 18.
7
Resistance to BET Inhibitor Leads to Alternative Therapeutic Vulnerabilities in Castration-Resistant Prostate Cancer.雄激素剥夺治疗耐药导致去势抵抗性前列腺癌的治疗新靶点
Cell Rep. 2018 Feb 27;22(9):2236-2245. doi: 10.1016/j.celrep.2018.02.011.
8
Therapeutic targeting of PP2A.靶向 PP2A 的治疗。
Int J Biochem Cell Biol. 2018 Mar;96:182-193. doi: 10.1016/j.biocel.2017.10.008. Epub 2017 Oct 26.
9
TMPRSS2-ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer.TMPRSS2-ERG 融合共同募集主转录因子并在原发性前列腺癌中激活 NOTCH 信号通路。
Nat Genet. 2017 Sep;49(9):1336-1345. doi: 10.1038/ng.3930. Epub 2017 Aug 7.
10
Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer.前列腺癌中ERG基因融合产物的拟肽抑制剂的研发
Cancer Cell. 2017 Apr 10;31(4):532-548.e7. doi: 10.1016/j.ccell.2017.02.017. Epub 2017 Mar 23.