Polo-like kinase 1 (Plk1), a crucial regulator of cell-cycle progression, is overexpressed in multiple types of cancers and has been proven to be a potent and promising target for cancer treatment. In case of prostate cancer, we once showed that antineoplastic activity of Plk1 inhibitor is largely due to inhibition of androgen receptor (AR) signaling. However, we also discovered that Plk1 inhibition causes activation of the β-catenin pathway and increased expression of c-MYC, eventually resulting in resistance to Plk1 inhibition. JQ1, a selective small-molecule inhibitor targeting the amino-terminal bromodomains of BRD4, has been shown to dramatically inhibit c-MYC expression and AR signaling, exhibiting antiproliferative effects in a range of cancers. Because c-MYC and AR signaling are essential for prostate cancer initiation and progression, we aim to test whether targeting Plk1 and BRD4 at the same time is an effective approach to treat prostate cancer. Herein, we show that a combination of Plk1 inhibitor GSK461364A and BRD4 inhibitor JQ1 had a strong synergistic effect on castration-resistant prostate cancer (CRPC) cell lines, as well as in CRPC xenograft tumors. Mechanistically, the synergistic effect is likely due to two reasons: (i) Plk1 inhibition results in the accumulation of β-catenin in the nucleus, thus elevation of c-MYC expression, whereas JQ1 treatment directly suppresses c-MYC transcription; (ii) Plk1 and BRD4 dual inhibition acts synergistically in inhibition of AR signaling. Mol Cancer Ther; 17(7); 1554–65. ©2018 AACR.

中文翻译：

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Plk1 抑制增强 BET 表观遗传 Reader 阻断在去势抵抗性前列腺癌中的功效


Polo 样激酶 1 (Plk1) 是细胞周期进展的关键调节因子，在多种类型的癌症中过度表达，并已被证明是癌症治疗的有效且有前景的靶标。就前列腺癌而言，我们曾经证明 Plk1 抑制剂的抗肿瘤活性很大程度上是由于雄激素受体 (AR) 信号传导的抑制。然而，我们还发现 Plk1 抑制会导致 β-catenin 通路激活并增加 c-MYC 表达，最终导致对 Plk1 抑制的抵抗。 JQ1 是一种针对 BRD4 氨基末端溴结构域的选择性小分子抑制剂，已被证明可以显着抑制 c-MYC 表达和 AR 信号传导，在多种癌症中表现出抗增殖作用。由于 c-MYC 和 AR 信号传导对于前列腺癌的发生和进展至关重要，因此我们的目的是测试同时靶向 Plk1 和 BRD4 是否是治疗前列腺癌的有效方法。在此，我们证明 Plk1 抑制剂 GSK461364A 和 BRD4 抑制剂 JQ1 的组合对去势抵抗性前列腺癌 (CRPC) 细胞系以及 CRPC 异种移植肿瘤具有很强的协同作用。从机制上讲，协同效应可能是由于两个原因：（i）Plk1抑制导致β-catenin在细胞核中积累，从而升高c-MYC表达，而JQ1处理直接抑制c-MYC转录； (ii) Plk1 和 BRD4 双重抑制在抑制 AR 信号传导中发挥协同作用。摩尔癌症治疗； 17(7)； 1554–65。 ©2018 AACR。