LNCaP公司
生存素
蛋白激酶B
前列腺癌
癌症研究
PARP抑制剂
PLK1
奥拉帕尼
体内
激酶
生长抑制
药理学
癌症
PTEN公司
PI3K/AKT/mTOR通路
细胞凋亡
医学
化学
生物
聚ADP核糖聚合酶
内科学
细胞周期
生物化学
酶
生物技术
聚合酶
作者
Mannan Nouri,Andreas Varkaris,Maya Ridinger,Susan L. Dalrymple,C. A. Dennehy,John T. Isaacs,David J. Einstein,W. Nathaniel Brennen,Steven P. Balk
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2024-06-19
卷期号:: OF1-OF14
标识
DOI:10.1158/1535-7163.mct-23-0933
摘要
Abstract Polo-like kinase 1 (PLK1) inhibitors have had limited antitumor efficacy as single agents, and focus of current efforts is on combination therapies. We initially confirmed that the PLK1-specific inhibitor onvansertib (ONV) could enhance responses to a PARP inhibitor (olaparib) in prostate cancer xenografts. To identify more effective combinations, we screened a library of bioactive compounds for efficacy in combination with ONV in LNCaP prostate cancer cells, which identified a series of compounds including multiple AKT inhibitors. We confirmed in vitro synergy between ONV and the AKT inhibitor ipatasertib (IPA) and found that the combination increased apoptosis. Mechanistic studies showed that ONV increased expression of the antiapoptotic protein SURVIVIN and that this was mitigated by IPA. Studies in three PTEN-deficient prostate cancer xenograft models showed that cotreatment with IPA and ONV led to significant tumor growth inhibition compared with monotherapies. Together, these in vitro and in vivo studies demonstrate that the efficacy of PLK1 antagonists can be enhanced by PARP or AKT inhibition and support further development of these combination therapies.
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