SOX2 utilizes FOXA1 as a heteromeric transcriptional partner to drive proliferation in therapy-resistant prostate cancer

Phoenix, J. T.; Budreika, A.; Schmeck, D. A.; Kostlan, R. J.; Ferrari, M. G.; Young, K. S.; Rogers, C. S.; Deegan, C. D.; Bergom, H. E.; Boytim, E.; Brown, R. M.; Bienko, M. W.; Walewicz, J. A.; Bhagi, S. K.; Ellis, L.; Antonarakis, E. S.; Drake, J. M.; Bawa, P. S.; Vellky, J. E.; Williams, A.; Reizine, N. M.; Rennhack, J. P.; Fanning, S. W.; Hwang, J. H.; Szmulewitz, R. Z.; Vander Griend, D. J.; Kregel, S.

doi:10.1101/2025.07.18.664790

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bioRxiv · 10.1101/2025.07.18.664790

SOX2 utilizes FOXA1 as a heteromeric transcriptional partner to drive proliferation in therapy-resistant prostate cancer

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Abstract

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.

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Phoenix, J. T., Budreika, A., Schmeck, D. A., Kostlan, R. J., Ferrari, M. G., Young, K. S., Rogers, C. S., Deegan, C. D., Bergom, H. E., Boytim, E., Brown, R. M., Bienko, M. W., Walewicz, J. A., Bhagi, S. K., Ellis, L., Antonarakis, E. S., Drake, J. M., Bawa, P. S., Vellky, J. E., Williams, A., Reizine, N. M., Rennhack, J. P., Fanning, S. W., Hwang, J. H., Szmulewitz, R. Z., Vander Griend, D. J., Kregel, S.. 2025-07-19. SOX2 utilizes FOXA1 as a heteromeric transcriptional partner to drive proliferation in therapy-resistant prostate cancer. https://doi.org/10.1101/2025.07.18.664790

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