Dynamic Reprogramming of Immune-Related Signaling During Progression to Enzalutamide Resistance in Prostate Cancer.

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Androgen receptor (AR) inhibitors like enzalutamide can drive prostate cancer to neuroendocrine prostate cancer (NEPC).
• The role of immune signaling in enzalutamide-induced lineage plasticity is not well understood.

Purpose of the Study:

• To investigate the impact of enzalutamide on immune signaling pathways during prostate cancer progression.
• To explore the potential of targeting immune pathways to overcome enzalutamide resistance and lineage plasticity.

Main Methods:

• Transcriptomic analysis of patient samples and cell lines.
• Assessment of interferon (IFN) and interleukin (IL) signaling pathways (IFNγ, IFNα, IL6-JAK-STAT3).
• Functional assays evaluating cytokine response and STAT1 inhibition with fludarabine.

Main Results:

• Immune pathways (IFNγ, IFNα, IL6-JAK-STAT3) were suppressed in NEPC and enzalutamide-resistant cells.
• Early enzalutamide treatment enhanced IFNγ and IL6 responsiveness and activated JAK/STAT signaling.
• Early-stage cells showed sensitivity to STAT1 inhibition, which was lost in resistant cells.

Conclusions:

• Enzalutamide initially enhances immune response but resistance involves immune suppression and plasticity.
• A therapeutic window exists for combining enzalutamide with STAT inhibitors to prevent resistance and plasticity.