Selective Actionable and Druggable Protein Kinases Drive the Progression of Neuroendocrine Prostate Cancer
Selective Actionable and Druggable Protein Kinases Drive the Progression of Neuroendocrine Prostate Cancer
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选择性可操作和可药物蛋白激酶驱动神经内分泌前列腺癌的进展
DOI：
10.1089/dna.2018.4193
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发表时间：
2018
影响因子：
3.1
通讯作者：
Xu Yong
中科院分区：
文献类型：
--
作者：
Lu Chao;Qie Yunkai;Liu Shenglai;Wu Changli;Zhang Zhihong;Liu Ranlu;Yang Kuo;Hu Hailong;Xu Yong
目前晚期前列腺癌（PCa）的临床抗雄激素治疗导致神经内分泌前列腺癌（NEPC）的发病率增加，NEPC是一种组织学变体，表现出雄激素受体水平降低和神经内分泌标志物表达降低。NEPC发展的潜在机制知之甚少。利用一组来自一个经过充分验证的NEPC异种移植模型的可用数据，分析蛋白激酶（PK）在NEPC发生中的确切作用。从NEPC转分化过程中发生剧烈变化的PK中筛选出54个可采取行动和药物治疗的PK，主要富集在PI 3 K-Akt、mTOR和MAPK信号通路中。进一步分析上述信号通路的相互作用，最终筛选出10个可能成为NEPC发生和治疗的驱动因子和治疗靶点的PK。体外实验结果表明，NEPC转分化过程中PK表达的变化趋势可以在不同恶性程度的PCa细胞系中重现。预测的激酶靶点在限制PC 3细胞生长中表现出不同的敏感性。选择性可作用和可药物化的PK可能在NEPC的进展中起驱动作用，其中大多数可作为临床实践中潜在的治疗靶点。
Current clinical anti-androgen therapies in advanced prostate cancer (PCa) are driving an increased incidence of neuroendocrine prostate cancer (NEPC), a histological variant exhibiting reduced androgen receptor levels and expression of neuroendocrine markers. The mechanisms underlying the development of NEPC are poorly understood. A set of available data from a well-validated xenograft model of NEPC was used to analyze the exact role of protein kinase (PK) played in the development of NEPC. Fifty-four actionable and druggable PKs, mainly enriched inPI3K-Akt,mTOR, andMAPKsignaling pathways, were screened out from the drastically changed PKs during NEPC transdifferentiation. Further analysis based on the crosstalk of these above signaling pathways finally singled out 10 PKs considered drivers and therapeutic targets in the development and treatment of NEPC.In vitro, the variation trend of PK expression observed during NEPC transdifferentiation could be recapitulated in PCa cell lines with different malignant degree. The predicted kinase targets exhibited different sensibilities in the restriction of PC3 cell growth. Selective actionable and druggable PKs may act as drivers in the progression of NEPC, and most of them can be used as potential therapeutic targets in clinical practice.