Karanika Styliani, Karantanos Theodoros, Li Likun, Wang Jianxiang, Park Sanghee, Yang Guang, Zuo Xuemei, Song Jian H, Maity Sankar N, Manyam Ganiraju C, Broom Bradley, Aparicio Ana M, Gallick Gary E, Troncoso Patricia, Corn Paul G, Navone Nora, Zhang Wei, Li Shuhua, Thompson Timothy C
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77230, USA.
Cell Rep. 2017 Feb 21;18(8):1970-1981. doi: 10.1016/j.celrep.2017.01.072.
Cell division cycle 6 (CDC6), an androgen receptor (AR) target gene, is implicated in regulating DNA replication and checkpoint mechanisms. CDC6 expression 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 with the AR signaling inhibitor enzalutamide (ENZ) and the Chk1/2 inhibitor 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.
细胞分裂周期6（CDC6）是一种雄激素受体（AR）靶基因，与调节DNA复制和检查点机制有关。在前列腺癌（PCa）进展过程中，CDC6表达增加，且在PCa组织中与AR呈正相关。AR或CDC6敲低，联合Chk1/2抑制剂AZD7762，会导致TopBP1-ATR-Chk1信号传导减弱，DNA损伤生物标志物共济失调毛细血管扩张症突变（ATM）磷酸化显著增加，并协同提高治疗效果。AR信号抑制剂恩杂鲁胺（ENZ）与Chk1/2抑制剂AZD7762联合治疗在抑制AR-CDC6-ATR-Chk1信号传导、诱导ATM磷酸化以及在VCaP（突变型p53）和LNCaP-C4-2b（野生型p53）细胞中诱导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信号传导，为AR阳性、转移性、去势抵抗性PCa引入了一种治疗策略，而不考虑p53状态。
