Xie Jingjing, He Hao, Kong Wenna, Li Ziwen, Gao Zhenting, Xie Daoqing, Sun Lin, Fan Xiaofei, Jiang Xiangqing, Zheng Qiangang, Li Guo, Zhu Jidong, Zhu Guangya
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Etern Biopharma, Shanghai, China.
Nat Chem Biol. 2022 Dec;18(12):1341-1350. doi: 10.1038/s41589-022-01151-y. Epub 2022 Oct 13.
Patients with castration-resistant prostate cancer inevitably acquire resistance to antiandrogen therapies in part because of androgen receptor (AR) mutations or splice variants enabling restored AR signaling. Here we show that ligand-activated AR can form transcriptionally active condensates. Both structured and unstructured regions of AR contribute to the effective phase separation of AR and disordered N-terminal domain plays a predominant role. AR liquid-liquid phase separation behaviors faithfully report transcriptional activity and antiandrogen efficacy. Antiandrogens can promote phase separation and transcriptional activity of AR-resistant mutants in a ligand-independent manner. We conducted a phase-separation-based phenotypic screen and identified ET516 that specifically disrupts AR condensates, effectively suppresses AR transcriptional activity and inhibits the proliferation and tumor growth of prostate cancer cells expressing AR-resistant mutants. Our results demonstrate liquid-liquid phase separation as an emerging mechanism underlying drug resistance and show that targeting phase separation may provide a feasible approach for drug discovery.
去势抵抗性前列腺癌患者不可避免地会对抗雄激素疗法产生耐药性，部分原因是雄激素受体（AR）突变或剪接变体导致AR信号恢复。在此，我们表明配体激活的AR可形成具有转录活性的凝聚物。AR的结构化和非结构化区域均有助于AR的有效相分离，且无序的N端结构域起主要作用。AR的液-液相分离行为如实反映了转录活性和抗雄激素疗效。抗雄激素可通过非配体依赖的方式促进AR耐药突变体的相分离和转录活性。我们进行了基于相分离的表型筛选，鉴定出ET516，它能特异性破坏AR凝聚物，有效抑制AR转录活性，并抑制表达AR耐药突变体的前列腺癌细胞的增殖和肿瘤生长。我们的结果证明液-液相分离是耐药性的一种新机制，并表明靶向相分离可能为药物发现提供一种可行的方法。
