Department of Surgery, University of Melbourne, Parkville, Victoria, Australia.
Division of Bioinformatics, Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
JCO Precis Oncol. 2021 Jun 22;5. doi: 10.1200/PO.20.00337. eCollection 2021 Jun.
Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition.
We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing.
We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for , a key regulator of EMT reprogramming.
We show that EMT characterizes acutely resistant prostate tumors and that deletion of , a key transcriptional regulator of EMT, correlates with clinical response.
雄激素受体（AR）信号在前列腺癌进展中很重要，针对该途径的治疗方法是治疗晚期疾病 70 多年的主要方法。尽管通过多种特征明确的机制进行了去势，但肿瘤仍会进展；然而，对于决定短期途径抑制反应幅度的因素知之甚少。
我们评估了一种新型的 AR 靶向治疗（degarelix、abiraterone 和 bicalutamide）组合，并注意到患者对治疗的客观反应高度可变。为了研究在反应不佳的患者中导致治疗耐药性的原因，作为次要结果，我们使用全基因组和 RNA 测序全面描述了治疗前后的样本。
我们发现，短期治疗后的耐药性在分子上与典型的进行性去势抵抗性疾病不同，与转录重编程相关，向过渡性上皮-间充质转化（EMT）表型转变，而不是 AR 信号的上调。出乎意料的是，对治疗的耐受性似乎是默认状态，治疗反应与缺乏肿瘤细胞的流行程度相关， 是 EMT 重编程的关键调节因子。
我们表明 EMT 特征是急性耐药性前列腺肿瘤，并且 EMT 的关键转录调节剂 的缺失与临床反应相关。
