Background

Although androgen deprivation therapy is initially effective in controlling growth of hormone-naive prostate cancers (HNPCs) in patients, currently incurable castration-resistant prostate cancer (CRPC) inevitably develops.

Objective

To identify CRPC driver genes that may provide new targets to enhance CRPC therapy.

Design, setting, and participants

Patient-derived xenografts (PDXs) of HNPCs that develop CRPC following host castration were examined for changes in expression of genes at various time points after castration using transcriptome profiling analysis; particular attention was given to pre-CRPC changes in expression indicative of genes acting as potential CRPC drivers.

Outcome measurements and statistical analysis

The functionality of a potential CRPC driver was validated via its knockdown in cultured prostate cancer cells; its clinical relevance was established using data from prostate cancer patient databases.

Results and limitations

Eighty genes were found to be significantly upregulated at the CRPC stage, while seven of them also showed elevated expression prior to CRPC development. Among the latter, growth factor receptor bound protein 10 (GRB10) was the most significantly and consistently upregulated gene. Moreover, elevated GRB10 expression in clinical prostate cancer samples correlated with more aggressive tumor types and poorer patient treatment outcome. GRB10 knockdown markedly reduced prostate cancer cell proliferation and activity of AKT, a well-established CRPC mediator. A positive correlation between AKT activity and GRB10 expression was also found in clinical cohorts.

Conclusions

GRB10 acts as a driver of CRPC and sensitizes androgen receptor pathway inhibitors, and hence GRB10 targeting provides a novel therapeutic strategy for the disease.

Patient summary

Development of castration-resistant prostate cancer (CRPC) is a major problem in the management of the disease. Using state-of-the-art patient-derived hormone-naive prostate cancer xenograft models, we found and validated the growth factor receptor bound protein 10 gene as a driver of CRPC, indicating that it may be used as a new molecular target to enhance current CRPC therapy.

中文翻译：

---

患者来源的未经激素的前列腺癌异种移植模型显示出生长因子受体结合蛋白10作为驱动去势抵抗性前列腺癌发展的雄激素受体抑制基因。

背景

尽管雄激素剥夺疗法最初可有效控制患者中未使用过激素的前列腺癌（HNPC）的生长，但目前不可避免地会发展出无法治愈的去势抵抗性前列腺癌（CRPC）。

客观的

鉴定可能提供新靶点以增强CRPC治疗的CRPC驱动程序基因。

设计，设置和参与者

使用转录组谱分析分析了在去势后不同时间点发展CRPC的HNPC的患者源异种移植物（PDXs）的基因表达变化。特别注意了CRPC之前的表达变化，这些变化表明基因可能是潜在的CRPC驱动程序。

成果测量和统计分析

潜在的CRPC驱动程序的功能已通过在培养的前列腺癌细胞中的敲低进行了验证。使用前列腺癌患者数据库中的数据确定其临床相关性。

结果与局限性

发现有80个基因在CRPC阶段显着上调，而其中有7个基因在CRPC发育之前也表现出升高的表达。在后者中，生长因子受体结合蛋白10（GRB10）是最显着且持续上调的基因。此外，临床前列腺癌样品中GRB10表达升高与更具侵略性的肿瘤类型和较差的患者治疗结果相关。GRB10基因敲低显着降低了前列腺癌细胞的增殖和AKT（一种公认的CRPC介体）的活性。在临床队列中还发现AKT活性与GRB10表达之间呈正相关。

结论

GRB10充当CRPC的驱动程序，并使雄激素受体途径抑制剂致敏，因此GRB10靶向为该疾病提供了一种新颖的治疗策略。

病人总结

去势抵抗性前列腺癌（CRPC）的发展是该疾病管理中的主要问题。使用最新的患者来源的未经激素的前列腺癌异种移植模型，我们发现并验证了生长因子受体结合蛋白10基因作为CRPC的驱动程序，表明它可用作增强CRPC的新分子靶标。目前的CRPC治疗。