Combination therapy with androgen receptor N-terminal domain antagonist EPI-7170 and enzalutamide yields synergistic activity in AR-V7-positive prostate cancer.
Combination therapy with androgen receptor N-terminal domain antagonist EPI-7170 and enzalutamide yields synergistic activity in AR-V7-positive prostate cancer.
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DOI：
10.1002/1878-0261.12770
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发表时间：
2020-10
影响因子：
6.6
通讯作者：
Sadar MD
中科院分区：
文献类型：
--
作者：
Hirayama Y;Tam T;Jian K;Andersen RJ;Sadar MD
Ralaniten及其类似物（EPI）结合雄激素受体N末端结构域（AR-NTD），阻断全长AR（FL-AR）和AR剪接变体（AR-Vs）的转录活性。Enzalutamide（ENZ）升高AR-V7水平，导致耐药性和增殖增加。靶向AR-NTD以阻断FL-AR和AR-Vs与EPI联合ENZ导致ENZ抗性前列腺癌细胞增殖的协同抑制。 去势抵抗性前列腺癌（CRPC）对Enzalutamide和阿比特龙的耐药性涉及缺乏C末端配体结合结构域（LBD）的组成型活性截短雄激素受体（AR）剪接变体（AR-V）的表达。全长AR和截短的AR-V都需要一个功能性N末端结构域（NTD）来实现转录活性，从而为开发雷拉尼丁（EPI-002）作为AR-NTD的第一种拮抗剂提供了理论基础。在此，我们评价了下一代雷拉尼丁类似物（EPI-7170）单药治疗或与Enzalutamide联合治疗对Enzalutamide耐药的表达AR-V7的前列腺癌细胞的抗肿瘤作用。EPI-7170的效力比ralaniten提高了8-9倍。Enzalutamide可增加AR-V7水平及其靶基因表达。AR-V7的敲除恢复了对Enzalutamide的敏感性，表明AR-V7在耐药机制中的作用。EPI-7170抑制由全长AR和AR-V7转录调控的基因表达。EPI-7170和Enzalutamide联合给药可协同抑制Enzalutamide耐药细胞的增殖，这与细胞周期和克隆形成试验的结果一致。此外，该药物在Enzalutamide耐药CRPC临床前模型中增强了Enzalutamide的抗肿瘤作用。因此，靶向AR的NTD和LBD，从而阻断全长AR和AR-V的联合治疗有可能治疗Enzalutamide耐药CRPC。
Ralaniten and analogs (EPI) bind androgen receptor N‐terminal domain (AR‐NTD) to block the transcriptional activities of full‐length AR (FL‐AR) and AR splice variants (AR‐Vs). Enzalutamide (ENZ) elevates levels of AR‐V7 leading to resistance and increased proliferation. Targeting AR‐NTD to block FL‐AR and AR‐Vs with EPI in combination with ENZ resulted in synergistic inhibition of proliferation of ENZ‐resistant prostate cancer cells. Resistance of castration‐resistant prostate cancer (CRPC) to enzalutamide and abiraterone involves the expression of constitutively active, truncated androgen receptor (AR) splice variants (AR‐Vs) that lack a C‐terminal ligand‐binding domain (LBD). Both full‐length AR and truncated AR‐Vs require a functional N‐terminal domain (NTD) for transcriptional activity thereby providing rationale for the development of ralaniten (EPI‐002) as a first‐in‐class antagonist of the AR‐NTD. Here, we evaluated the antitumor effect of a next‐generation analog of ralaniten (EPI‐7170) as a monotherapy or in combination with enzalutamide in prostate cancer cells that express AR‐V7 that were resistant to enzalutamide. EPI‐7170 had 8–9 times improved potency compared to ralaniten. Enzalutamide increased levels of AR‐V7 and expression of its target genes. Knockdown of AR‐V7 restored sensitivity to enzalutamide, indicating a role for AR‐V7 in the mechanism of resistance. EPI‐7170 inhibited expression of genes transcriptionally regulated by full‐length AR and AR‐V7. A combination of EPI‐7170 and enzalutamide resulted in synergistic inhibition of proliferation of enzalutamide‐resistant cells that was consistent with results from cell cycle and clonogenic assays. In addition, this drug enhanced the antitumor effect of enzalutamide in enzalutamide‐resistant CRPC preclinical models. Thus, a combination therapy targeting both the NTD and LBD of AR, and thereby blocking both full‐length AR and AR‐Vs, has potential for the treatment of enzalutamide‐resistant CRPC.
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影响因子：
16.6
作者：
Liu C;Lou W;Yang JC;Liu L;Armstrong CM;Lombard AP;Zhao R;Noel ODV;Tepper CG;Chen HW;Dall'Era M;Evans CP;Gao AC
通讯作者：
Gao AC
影响因子：
--
作者：
Jones D;Wade M;Nakjang S;Chaytor L;Grey J;Robson CN;Gaughan L
通讯作者：
Gaughan L
影响因子：
7.7
作者：
Balbas MD;Evans MJ;Hosfield DJ;Wongvipat J;Arora VK;Watson PA;Chen Y;Greene GL;Shen Y;Sawyers CL
通讯作者：
Sawyers CL
雄激素受体剪接变体与组成性开放染色质结合并促进前列腺癌的阿比特龙耐药生长
影响因子：
14.9
作者：
He Y;Lu J;Ye Z;Hao S;Wang L;Kohli M;Tindall DJ;Li B;Zhu R;Wang L;Huang H
通讯作者：
Huang H
影响因子：
28.2
作者：
Korpal, Manav;Korn, Joshua M.;Zhu, Ping
通讯作者：
Zhu, Ping