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Targeting FOXA1 and FOXA2 disrupts the lineage-specific oncogenic output program in prostate cancer

Nicolo Formaggio1, Jacopo Sgrignani2, Gayathri Thillaiyampalam1

  • 1Institute of Oncology Research, Bellinzona, Switzerland; Università della Svizzera italiana, Faculty of Biomedical Sciences, Lugano, Switzerland.

Cell Reports
|September 27, 2025
PubMed

Insights

This study reveals that FOXA1 and FOXA2 transcription factors unexpectedly collaborate to drive prostate cancer cell growth. Targeting both FOXA1 and FOXA2 offers a promising therapeutic strategy for both androgen receptor-positive and -negative prostate cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Androgen receptor (AR) signaling is crucial in prostate cancer, with FOXA1 enabling its activation.
  • FOXA2 is expressed in advanced, lineage-plastic prostate cancers that have lost AR signaling.
  • The roles of FOXA1 and FOXA2 in prostate cancer, particularly in lineage-plastic subtypes, require further characterization.

Purpose of the Study:

  • To investigate the collaborative roles of FOXA1 and FOXA2 in prostate cancer.
  • To explore the therapeutic potential of targeting FOXA1 and FOXA2 in both AR-positive and AR-negative prostate cancers.

Main Methods:

  • Investigated the function of FOXA1 and FOXA2 in mediating cell proliferation in lineage-plastic cancer subtypes.
  • Utilized loss-of-function studies and pharmacologic inhibition to disrupt FOXA1 and FOXA2 activity.
  • Analyzed the impact of FOXA1/FOXA2 disruption on lineage-specific oncogenic transcription factors and cell-cycle progression.

Main Results:

  • Demonstrated an unexpected collaboration between FOXA1 and FOXA2 in driving AR-independent cell proliferation across different lineage-plastic cancer subtypes.
  • Showed that simultaneous loss-of-function or pharmacologic inhibition of FOXA1 and FOXA2 leads to the collapse of key oncogenic transcription factors.
  • Observed cell-cycle arrest following the disruption of FOXA1 and FOXA2.

Conclusions:

  • FOXA1 and FOXA2 play a collaborative role in AR-independent prostate cancer cell proliferation.
  • Joint targeting of FOXA1 and FOXA2 represents a druggable dependency for both AR-positive and AR-negative prostate cancers.
  • These findings open new therapeutic avenues for advanced and lineage-plastic prostate cancers.
Keywords:
CP: CancerFOXA1FOXA2androgen receptor independenceandrogen receptor signalinglineage plasticitypioneer transcription factorprostate cancersmall molecule inhibitor

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