Phoenix John T, Budreika Audris, Schmeck Devin A, Kostlan Raymond J, Ferrari Marina G, Young Kristen S, Rogers Charles S, Deegan Carleen D, Bienko Marcus W, Bergom Hannah E, Boytim Ella, Brown Ryan M, Walewicz Julia A, Bhagi Shreya K, Ellis Leigh, Antonarakis Emmanuel S, Drake Justin M, Bawa Pushpinder S, Vellky Jordan E, Williams Anthony, Rezine Natalie M, Rennhack Jonathan P, Fanning Sean W, Hwang Justin H, Szmulewitz Russell Z, Vander Griend Donald J, Kregel Steven
Department of Cancer Biology, Loyola University Chicago, Maywood, IL, USA.
Integrated Program in Biomedical Science, Biochemistry, Molecular and Cancer Biology, Loyola University Chicago, Maywood, IL, USA.
bioRxiv. 2025 Jul 19:2025.07.18.664790. doi: 10.1101/2025.07.18.664790.
Treatment options and diagnostic outlook for men with advanced, therapy resistant prostate cancer (PCa) are extremely poor; this is primarily due to the common lack of durable response to androgen receptor (AR) targeted therapies and phenotypic transdifferentiation into a particularly lethal subtype known as neuroendocrine prostate cancer (NEPC). In this study, we mechanistically determine that SOX2 (a transcription factor originally repressed by AR) physically binds and acts in a concerted manner with FOXA1 (a key AR pioneering cofactor) to regulate a subset of genes which promote cell cycle progression, and lineage plasticity in AR-refractory prostate cancers. Our findings assert the SOX2/FOXA1 interaction as an important mediator of resistance to AR-targeted therapy and a driver of NEPC and lineage plasticity; their coordinated action and downstream signaling offers a potential novel therapeutic opportunity in late-stage PCa.
晚期、对治疗耐药的前列腺癌（PCa）男性患者的治疗选择和诊断前景极为不佳；这主要是由于对雄激素受体（AR）靶向治疗普遍缺乏持久反应，以及表型转分化为一种特别致命的亚型，即神经内分泌前列腺癌（NEPC）。在本研究中，我们从机制上确定，SOX2（一种最初被AR抑制的转录因子）与FOXA1（一种关键的AR先驱辅助因子）物理结合并协同作用，以调控一组促进细胞周期进程以及AR难治性前列腺癌中的谱系可塑性的基因。我们的研究结果表明，SOX2/FOXA1相互作用是对AR靶向治疗耐药的重要介导因素，也是NEPC和谱系可塑性的驱动因素；它们的协同作用和下游信号传导为晚期PCa提供了一个潜在的新治疗机会。
