Dual FOXA1/FOXA2 Targeting to Shut Down Lineage-Plastic Castration-Resistant Prostate Cancer

Targeting FOXA1 and FOXA2 in castration-resistant prostate cancer represents a new way of attacking the disease at the level of its lineage “identity” rather than only at the androgen receptor. FOXA1 and FOXA2 belong to a family of pioneer transcription factors. These pioneer transcription factors unlock tightly packed DNA, creating access for other proteins that control how cancer cells survive and grow. In early hormone-sensitive disease, FOXA1 guides the androgen receptor to its targets, fueling classic prostate cancer growth. In advanced stages where tumors escape hormone therapy, FOXA2 steps in to pioneer new survival pathways linked to lineage plasticity and neuroendocrine features.

The central observation of a recent research, published on Cell, is that FOXA1 and FOXA2 do not simply act in separate disease phases but can collaborate in castration-resistant models that have undergone lineage plasticity. These advanced tumors have lost androgen receptor signaling but stay highly aggressive, often developing neuroendocrine or small-cell features that resist standard hormone treatments. Here, FOXA2 accesses developmental DNA regions and works with factors like AP-1 and ASCL1 to rewire gene expression, while FOXA1 provides ongoing support for this mixed, plastic cancer state. Together, FOXA1 and FOXA2 drive growth independent of hormones in late-stage, treatment-resistant disease.

By blocking both FOXA1 and FOXA2, through genetic knockout or drugs, the cancer’s lineage-specific growth network falls apart. Without these pioneer factors, key transcription factors like androgen receptor (in AR-positive cells) or AP-1 and ASCL1 (in AR-negative, plastic cells) lose DNA access and can’t drive their cancer genes anymore. This halts cell division as tumors stop cycling through growth phases. The effect works across castration-resistant types, from AR-retaining models to fully AR-independent neuroendocrine states.

​Transcription factors like FOXA1 and FOXA2 have been considered hard drug targets because they lack the usual pockets small molecules bind to. The new findings show drugs can still disrupt them in lab models, mimicking genetic knockout by shutting down cancer gene networks and stopping growth. This fits the trend of targeting gene control hubs instead of just receptors in advanced prostate cancer. Dual targeting prevents tumors from switching between FOXA1-driven hormone-dependent growth and FOXA2-driven hormone-independent escape.

This research, while promising, remains at the cellular and organoid stage (very early preclinical development). The findings are significant, but clinical applications remain years away.

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