Ku Sheng Yu, Rosario Spencer, Wang Yanqing, Mu Ping, Seshadri Mukund, Goodrich Zachary W, Goodrich Maxwell M, Labbé David P, Gomez Eduardo Cortes, Wang Jianmin, Long Henry W, Xu Bo, Brown Myles, Loda Massimo, Sawyers Charles L, Ellis Leigh, Goodrich David W
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute (RPCI), Buffalo, NY 14263, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
Science. 2017 Jan 6;355(6320):78-83. doi: 10.1126/science.aah4199.
Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting that lineage plasticity facilitates therapeutic resistance. The mechanisms underlying prostate cancer lineage plasticity are incompletely understood. Studying mouse models, we demonstrate that Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates that mouse tumors resemble human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors such as Ezh2 and Sox2. Clinically relevant Ezh2 inhibitors restore androgen receptor expression and sensitivity to antiandrogen therapy. These findings uncover genetic mutations that enable prostate cancer progression; identify mouse models for studying prostate cancer lineage plasticity; and suggest an epigenetic approach for extending clinical responses to antiandrogen therapy.
抗雄激素治疗后复发的前列腺癌可表现出组织学变异，其谱系标志物表达发生改变，这表明谱系可塑性促进了治疗抵抗。前列腺癌谱系可塑性的潜在机制尚未完全明确。通过对小鼠模型的研究，我们证明Rb1缺失促进了由Pten突变引发的前列腺腺癌的谱系可塑性和转移。Trp53的额外缺失导致对抗雄激素治疗产生抗性。基因表达谱分析表明，小鼠肿瘤类似于人类前列腺癌神经内分泌变体；小鼠和人类肿瘤均表现出表观遗传重编程因子（如Ezh2和Sox2）的表达增加。临床相关的Ezh2抑制剂可恢复雄激素受体表达，并恢复对抗雄激素治疗的敏感性。这些发现揭示了促使前列腺癌进展的基因突变；确定了用于研究前列腺癌谱系可塑性的小鼠模型；并提出了一种表观遗传方法来延长对抗雄激素治疗的临床反应。
