恩扎鲁胺是一种第二代内分泌治疗药物，用于前列腺癌（PCa），是合成雄激素受体拮抗剂中杰出的代表。目前，缺乏恩扎鲁胺诱导的基因特征（ENZ-sig）来预测PCa的进展和无复发生存期（RFS）。恩扎鲁胺诱导的候选标记来自于单细胞RNA测序分析，整合了三种恩扎鲁胺刺激模型（0小时、48小时和168小时恩扎鲁胺刺激）。ENZ-sig基于与The Cancer Genome Atlas中RFS相关的候选基因构建，利用最小绝对收缩和选择算子法。ENZ-sig在GSE70768、GSE94767、E-MTAB-6128、DFKZ、GSE21034和GSE70769数据集中得到进一步验证。采用生物学富集分析发现单个细胞RNA测序和大规模RNA测序中高ENZ-sig和低ENZ-sig之间的潜在机制。我们确定了一种通过恩扎鲁胺刺激诱导的异质性亚组，并发现了53个与轨迹进展和恩扎鲁胺刺激相关的恩扎鲁胺诱导的候选标记。候选基因进一步缩小到10个与PCa的RFS相关的基因。一个10基因的预后模型（ENZ-sig）-IFRD1、COL5A2、TUBA1A、CFAP69、TMEM388、ACPP、MANEA、FOSB、SH3BGRL和ST7-被构建用于预测PCa的RFS。ENZ-sig的有效和稳健预测能力在六个独立数据集中得到验证。生物学富集分析表明，在高ENZ-sig中差异表达的基因在细胞周期相关途径中更为活跃。PCa中高ENZ-sig患者对细胞周期靶向药物（MK-1775、AZD7762和MK-8776）比低ENZ-sig患者更敏感。我们的结果为ENZ-sig在PCa预后和恩扎鲁胺与细胞周期靶向复合物联合治疗策略中的潜在效用提供了证据和见解。版权所有©2023 Feng, Deng, Tang, Cai, Li, Liu, Wan, He, Zeng, Ye, Han and Zhong。

Enzalutamide, as a second-generation endocrine therapy drug for prostate cancer (PCa), is prominent representative among the synthetic androgen receptor antagonists. Currently, there is lack of enzalutamide-induced signature (ENZ-sig) for predicting progression and relapse-free survival (RFS) in PCa.Enzalutamide-induced candidate markers were derived from single-cell RNA sequencing analysis integrating three enzalutamide-stimulated models (0-, 48-, and 168-h enzalutamide stimulation). ENZ-sig was constructed on the basis of candidate genes that were associated with RFS in The Cancer Genome Atlas leveraging least absolute shrinkage and selection operator method. The ENZ-sig was further validated in GSE70768, GSE94767, E-MTAB-6128, DFKZ, GSE21034, and GSE70769 datasets. Biological enrichment analysis was used to discover the underlying mechanism between high ENZ-sig and low ENZ-sig in single-cell RNA sequencing and bulk RNA sequencing.We identified a heterogenous subgroup that induced by enzalutamide stimulation and found 53 enzalutamide-induced candidate markers that are related to trajectory progression and enzalutamide-stimulated. The candidate genes were further narrowed down into 10 genes that are related to RFS in PCa. A 10-gene prognostic model (ENZ-sig)-IFRD1, COL5A2, TUBA1A, CFAP69, TMEM388, ACPP, MANEA, FOSB, SH3BGRL, and ST7-was constructed for the prediction of RFS in PCa. The effective and robust predictability of ENZ-sig was verified in six independent datasets. Biological enrichment analysis revealed that differentially expressed genes in high ENZ-sig were more activated in cell cycle-related pathway. High-ENZ-sig patients were more sensitive to cell cycle-targeted drugs (MK-1775, AZD7762, and MK-8776) than low-ENZ-sig patients in PCa.Our results provided evidence and insight on the potential utility of ENZ-sig in PCa prognosis and combination therapy strategy of enzalutamide and cell cycle-targeted compounds in treating PCa.Copyright © 2023 Feng, Deng, Tang, Cai, Li, Liu, Wan, He, Zeng, Ye, Han and Zhong.