PURPOSE Small-cell neuroendocrine prostate cancer (SCNPC) exhibits an aggressive clinical course and incidence rates seem to be increasing following resistance to potent androgen receptor (AR) antagonists. Currently, treatment options are limited and few model systems are available to identify new approaches for treatment. We sought to evaluate commonalities between SCNPC and other aggressive neuroendocrine carcinomas to identify therapeutic targets. EXPERIMENTAL DESIGN We generated whole transcriptome RNA-sequencing data from AR-active prostate cancers (ARPCs) and SCNPCs from tumors collected at rapid autopsy and two other neuroendocrine carcinomas, Merkel cell carcinoma (MCC), and small-cell lung cancer. We performed cross-tumor comparisons to identify conserved patterns of expression of druggable targets. We tested inhibitors to highly upregulated drug targets in a panel of prostate cancer cell lines and in vivo patient-derived xenograft (PDX) models. RESULTS We identified BCL2 as highly upregulated in SCNPC compared with ARPC. Inhibitors targeting BCL2 induced apoptotic cell death in SCNPC cell lines at nanomolar concentrations while ARPC cell lines were resistant. Treatment with the BCL2 inhibitor navitoclax leads to a reduction of growth of SCNPC PDX tumors in vivo, whereas ARPC PDX models were more resistant. We identified Wee1 as a second druggable target upregulated in SCNPC. Treatment with the combination of navitoclax and the Wee1 inhibitor AZD-1775 repressed the growth of SCNPC PDX resistant to single-agent BCL2 inhibitors. CONCLUSIONS The combination of BCL2 and Wee1 inhibition presents a novel therapeutic strategy for the treatment of SCNPC.

中文翻译：

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小细胞神经内分泌前列腺癌治疗脆弱性的鉴定。


目的小细胞神经内分泌前列腺癌 (SCNPC) 表现出侵袭性的临床病程，并且在对强效雄激素受体 (AR) 拮抗剂产生耐药性后，发病率似乎有所增加。目前，治疗选择有限，并且很少有模型系统可用于确定新的治疗方法。我们试图评估 SCNPC 和其他侵袭性神经内分泌癌之间的共性，以确定治疗靶点。实验设计我们从快速尸检中收集的肿瘤中的 AR 活性前列腺癌 (ARPC) 和 SCNPC 以及其他两种神经内分泌癌、默克尔细胞癌 (MCC) 和小细胞肺癌中生成了全转录组 RNA 测序数据。我们进行了跨肿瘤比较，以确定可药物靶点的保守表达模式。我们在一组前列腺癌细胞系和体内患者来源的异种移植（PDX）模型中测试了高度上调药物靶标的抑制剂。结果我们发现，与 ARPC 相比，SCNPC 中 BCL2 高度上调。针对 BCL2 的抑制剂在纳摩尔浓度下会诱导 SCNPC 细胞系凋亡细胞死亡，而 ARPC 细胞系则具有抗性。使用 BCL2 抑制剂 navitoclax 治疗可减少体内 SCNPC PDX 肿瘤的生长，而 ARPC PDX 模型的耐药性更强。我们确定 Wee1 是 SCNPC 中上调的第二个可药物靶点。 navitoclax 和 Wee1 抑制剂 AZD-1775 联合治疗可抑制对单药 BCL2 抑制剂耐药的 SCNPC PDX 的生长。结论 BCL2 和 Wee1 抑制的组合为 SCNPC 的治疗提供了一种新的治疗策略。