Targeting DNA Damage Response in Prostate Cancer by Inhibiting Androgen Receptor-CDC6-ATR-Chk1 Signaling.
Targeting DNA Damage Response in Prostate Cancer by Inhibiting Androgen Receptor-CDC6-ATR-Chk1 Signaling.
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DOI：
10.1016/j.celrep.2017.01.072
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发表时间：
2017-02-21
期刊：
影响因子：
8.8
通讯作者：
Thompson TC
中科院分区：
文献类型：
--
作者：
Karanika S;Karantanos T;Li L;Wang J;Park S;Yang G;Zuo X;Song JH;Maity SN;Manyam GC;Broom B;Aparicio AM;Gallick GE;Troncoso P;Corn PG;Navone N;Zhang W;Li S;Thompson TC
细胞分裂周期蛋白6（CDC6）是雄激素受体（AR）的一个靶基因，参与调节DNA复制和检查点机制。在前列腺癌（PCa）进展过程中，CDC6表达增加，并且在PCa组织中与AR呈正相关。抑制AR或CDC6，同时使用Chk1/2抑制剂AZD7762，会导致TopBP1 - ATR - Chk1信号通路减弱，共济失调毛细血管扩张突变（ATM）磷酸化显著增加（ATM磷酸化是DNA损伤的一个生物标志物），并且协同提高治疗效果。使用恩杂鲁胺（ENZ）抑制AR，同时使用AZD7762抑制Chk1/2，在VCaP（p53突变型）和LNCaP - C4 - 2b（p53野生型）细胞中，在抑制AR/CDC6 - ATR - Chk1信号通路、诱导ATM磷酸化以及促进细胞凋亡方面表现出协同作用。CDC6过表达显著降低了ENZ和AZD7762诱导的细胞凋亡。在AR阳性动物异种移植模型中显示出相加或协同的治疗活性。这些发现具有重要的临床意义，因为它们通过靶向AR/CDC6 - ATR - Chk1信号通路，为AR阳性的转移性去势抵抗性前列腺癌引入了一种治疗策略，无论p53状态如何。
Cell division cycle 6 (CDC6), an androgen receptor (AR) target gene, is implicated in regulating DNA replication and checkpoint mechanisms. CDC6 is increased during prostate cancer (PCa) progression and positively correlates with AR in PCa tissues. AR or CDC6 knockdown together with AZD7762, a Chk1/2 inhibitor, results in decreased TopBP1-ATR-Chk1 signaling and markedly increased ataxia-telangiectasia mutated (ATM) phosphorylation, a biomarker of DNA damage, and synergistically increases treatment efficacy. Combination treatment of AR with enzalutamide (ENZ) and Chk1/2 inhibition with AZD7762 demonstrates synergy with regard to inhibition of AR/CDC6-ATR-Chk1 signaling, ATM phosphorylation induction, and apoptosis in VCaP (mutant p53) and LNCaP-C4-2b (wild-type p53) cells. CDC6 overexpression significantly reduced ENZ and AZD7762-induced apoptosis. Additive or synergistic therapeutic activities are demonstrated in AR-positive animal xenograft models. These findings have important clinical implications since they introduce a therapeutic strategy for AR-positive metastatic castration-resistant PCa, regardless of p53 status, through targeting AR/CDC6-ATR-Chk1 signaling.