Dahiya Ujjwal R, Kumari Sangeeta, Singh Nidhi, Rawat Chitra, Cortes Eduardo, Ghanem Yara, Corey Eva, Dehm Scott M, Willard Belinda, Alshalalfa Mohammed, Davicioni Elai, McKenney Jesse, Weight Christopher, Haywood Samuel C, Liu Song, Liu Tao, Heemers Hannelore V
Department of Cancer Biology, Cleveland Clinic, Cleveland, OH 44195, USA.
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
Cell Rep. 2025 Sep 23;44(9):116235. doi: 10.1016/j.celrep.2025.116235. Epub 2025 Sep 9.
Continued reliance on the androgen receptor (AR) after androgen deprivation therapy (ADT) fails causes 35,000 American prostate cancer (CaP) deaths annually. Targeting the AR's transcriptional activity could overcome this acquired resistance, but has been challenging. We demonstrate the therapeutic potential of disrupting interactions between the AR and its coregulator WDR77. WDR77 stimulated CaP growth, and its overexpression was associated with worse patient survival. AR and WDR77 cistromes overlapped considerably, and AR- and WDR77-bound genes correlated with aggressive CaP features. Direct WDR77-AR interaction occurred, which, when disrupted, prevented AR-WDR77 complex formation, reduced AR DNA-binding and AR-dependent gene expression, and decreased cell proliferation to the same extent as ADT. Such interference inhibited cell growth by ADT-resistant AR action and after ADT-resistance without impacting AR-negative CaP or benign cells. Blocking AR-WDR77 cooperation also delayed the growth of organoids from patient-derived xenografts and fresh CaP specimens. Disrupting coregulator control over AR action may thus improve survival from ADT-resistant CaP.
雄激素剥夺疗法（ADT）失败后持续依赖雄激素受体（AR）每年导致35000名美国前列腺癌（CaP）患者死亡。靶向AR的转录活性可克服这种获得性耐药，但颇具挑战性。我们证明了破坏AR与其共调节因子WDR77之间相互作用的治疗潜力。WDR77刺激CaP生长，其过表达与患者较差的生存率相关。AR和WDR77的染色质免疫沉淀测序结果有相当大的重叠，且与AR和WDR77结合的基因与侵袭性CaP特征相关。AR与WDR77直接相互作用，当这种相互作用被破坏时，可阻止AR-WDR77复合物形成，减少AR与DNA的结合及AR依赖的基因表达，并使细胞增殖减少至与ADT相同的程度。这种干扰通过ADT耐药的AR作用抑制细胞生长，且在出现ADT耐药后仍起作用，同时不影响AR阴性的CaP细胞或良性细胞。阻断AR-WDR77的协同作用还可延缓源自患者异种移植瘤和新鲜CaP标本的类器官生长。因此，破坏共调节因子对AR作用的控制可能会改善ADT耐药CaP患者的生存率。
