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.
bioRxiv : the preprint server for biology. 2025 Jul 19*** epublish ***
John T Phoenix, Audris Budreika, Devin A Schmeck, Raymond J Kostlan, Marina G Ferrari, Kristen S Young, Charles S Rogers, Carleen D Deegan, Marcus W Bienko, Hannah E Bergom, Ella Boytim, Ryan M Brown, Julia A Walewicz, Shreya K Bhagi, Leigh Ellis, Emmanuel S Antonarakis, Justin M Drake, Pushpinder S Bawa, Jordan E Vellky, Anthony Williams, Natalie M Rezine, Jonathan P Rennhack, Sean W Fanning, Justin H Hwang, Russell Z Szmulewitz, Donald J Vander Griend, Steven Kregel