Abstract：
The development of androgen receptor signaling inhibitor (ARSI) drug resistance in prostate cancer (PC) remains therapeutically challenging. Our group has described the role of sex determining region Y-box 2 (SOX2) overexpression in ARSI-resistant PC. Continuing this work, we report that NR3C1, the gene encoding glucocorticoid receptor (GR), is a novel SOX2 target in PC, positively regulating its expression. Similar to ARSI treatment, SOX2-positive PC cells are insensitive to GR signaling inhibition using a GR modulating therapy. To understand SOX2-mediated nuclear hormone receptor signaling inhibitor (NHRSI) insensitivity, we performed RNA-seq in SOX2-positive and -negative PC cells following NHRSI treatment. RNA-seq prioritized differentially regulated genes mediating the cell cycle, including G2 checkpoint WEE1 Kinase (WEE1) and cyclin-dependent kinase 1 (CDK1). Additionally, WEE1 and CDK1 were differentially expressed in PC patient tumors dichotomized by high vs low SOX2 gene expression. Importantly, pharmacological targeting of WEE1 (WEE1i) in combination with an ARSI or GR modulator re-sensitizes SOX2-positive PC cells to nuclear hormone receptor signaling inhibition in vitro, and WEE1i combined with ARSI significantly slowed tumor growth in vivo. Collectively, our data suggest SOX2 predicts NHRSI resistance, and simultaneously indicates the addition of WEE1i to improve therapeutic efficacy of NHRSIs in SOX2-positive PC.
摘要：
前列腺癌（PC）中雄激素受体信号传导抑制剂（ARSI）耐药性的发展仍然具有治疗挑战性。我们小组描述了性别决定区Y-box2（SOX2）过表达在ARSI抗性PC中的作用。继续这项工作,我们报道NR3C1，编码糖皮质激素受体（GR）的基因，是PC中的一种新型SOX2靶标，积极调节其表达。类似于ARSI治疗，SOX2阳性PC细胞对使用GR调节疗法的GR信号传导抑制不敏感。了解SOX2介导的核激素受体信号抑制剂（NHRSI）的不敏感性，我们在NHRSI处理后的SOX2阳性和阴性PC细胞中进行了RNA-seq。RNA-seq优先的差异调节基因介导细胞周期，包括G2检查点WEE1激酶（WEE1）和细胞周期蛋白依赖性激酶1（CDK1）。此外,WEE1和CDK1在PC患者肿瘤中差异表达，由高和低SOX2基因表达区分。重要的是,WEE1（WEE1i）与ARSI或GR调节剂联合的药理学靶向使SOX2阳性PC细胞对核激素受体信号传导抑制在体外敏感，和WEE1i联合ARSI显著减缓体内肿瘤生长。总的来说，我们的数据表明SOX2预测NHRSI抗性，并且同时表明添加WEE1i以提高NHRSIs在SOX2阳性PC中的治疗功效。
