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Updated: Sep 11, 2025

Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
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SOX2 utilizes FOXA1 as a heteromeric transcriptional partner to drive proliferation in therapy-resistant prostate

John T Phoenix1,2, Audris Budreika1,2, Devin A Schmeck3

  • 1Department of Cancer Biology, Loyola University Chicago, Maywood, IL, USA.

Biorxiv : the Preprint Server for Biology
|August 12, 2025
PubMed

Insights

In advanced prostate cancer (PCa), SOX2 and FOXA1 proteins interact to drive resistance to androgen receptor (AR) therapies and promote lethal neuroendocrine prostate cancer (NEPC) by regulating cell cycle progression and plasticity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Advanced prostate cancer (PCa) presents poor treatment options due to therapy resistance.
  • Resistance is linked to androgen receptor (AR) targeted therapy failure and transdifferentiation to neuroendocrine prostate cancer (NEPC).

Purpose of the Study:

  • To mechanistically investigate the role of SOX2 and FOXA1 interaction in AR-refractory prostate cancer.
  • To identify novel therapeutic targets for advanced and therapy-resistant prostate cancer.

Main Methods:

  • Investigated the physical binding of transcription factor SOX2 with AR pioneering cofactor FOXA1.
  • Analyzed the regulation of gene subsets by the SOX2/FOXA1 complex in AR-refractory prostate cancer cells.

Main Results:

  • SOX2 physically binds and cooperates with FOXA1 in AR-refractory prostate cancers.
  • The SOX2/FOXA1 complex regulates genes promoting cell cycle progression and lineage plasticity.
  • This interaction is a key mediator of resistance to AR-targeted therapy and a driver of NEPC.

Conclusions:

  • The SOX2/FOXA1 interaction is a critical mechanism underlying therapeutic resistance and NEPC development in prostate cancer.
  • Targeting the SOX2/FOXA1 coordinated action presents a potential novel therapeutic strategy for late-stage prostate cancer.
Keywords:
ARASCL1CRPCFGFFGFRFOXA1NEPCProstate cancerROR1SOX2androgencastrationenzalutamidelineage plasticityneuroendocrinestem cells

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