Docetaxel chemotherapy in metastatic prostate cancer offers only a modest survival benefit because of emerging resistance. To identify candidate therapeutic gene targets, we applied a murine prostate cancer orthograft model that recapitulates clinical invasive prostate cancer in a genome-wide CRISPR/Cas9 screen under docetaxel treatment pressure. We identified 17 candidate genes whose suppression may enhance the efficacy of docetaxel, with transcription elongation factor A-like 1 (Tceal1) as the top candidate. TCEAL1 function is not fully characterised; it may modulate transcription in a promoter dependent fashion. Suppressed TCEAL1 expression in multiple human prostate cancer cell lines enhanced therapeutic response to docetaxel. Based on gene set enrichment analysis from transcriptomic data and flow cytometry, we confirmed that loss of TCEAL1 in combination with docetaxel leads to an altered cell cycle profile compared with docetaxel alone, with increased subG1 cell death and increased polyploidy. Here, we report the first in vivo genome-wide treatment sensitisation CRISPR screen in prostate cancer, and present proof of concept data on TCEAL1 as a candidate for a combinational strategy with the use of docetaxel.

中文翻译：

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体内 CRISPR/Cas9 敲除筛选：TCEAL1 沉默增强多西紫杉醇治疗前列腺癌的疗效。


由于耐药性的出现，多西紫杉醇化疗在转移性前列腺癌中只能提供有限的生存获益。为了确定候选治疗基因靶点，我们应用了小鼠前列腺癌正交移植模型，该模型在多西紫杉醇治疗压力下通过全基因组 CRISPR/Cas9 筛选重现了临床侵袭性前列腺癌。我们确定了 17 个候选基因，其抑制可能会增强多西紫杉醇的功效，其中转录延伸因子 A 样 1 ( Tceal1 ) 是最佳候选基因。 TCEAL1 功能尚未完全表征；它可以以启动子依赖性方式调节转录。抑制多种人前列腺癌细胞系中的 TCEAL1 表达可增强对多西紫杉醇的治疗反应。基于转录组数据和流式细胞术的基因集富集分析，我们证实，与单独使用多西紫杉醇相比，TCEAL1 缺失与多西紫杉醇联合使用会导致细胞周期谱发生改变，亚 G1 细胞死亡增加，多倍体增加。在这里，我们报告了前列腺癌中第一个体内全基因组治疗敏化 CRISPR 筛选，并提供了TCEAL1的概念数据证明，作为使用多西他赛的组合策略的候选者。