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

Prostate cancer is a prevalent and lethal cancer. Research groups at the Institute Of Oncology Research affiliated to USI (Prof. Theurillat) and Institute for Research in Biomedicine affiliated to USI (Dr. Cavalli) publish in Cell Reports the first-in-class inhibitors targeting FOXA1 and FOXA2, two key transcription factors driving prostate cancer progression thought to be undruggable thus far.

Activation of the androgen receptor (AR) is the key lineage-specific oncogenic pathway and the primary therapeutic target in prostate cancer. While AR signaling is enabled by the pioneer transcription factor FOXA1, its homolog FOXA2 is specifically expressed in advanced lineage-plastic prostate cancers that have lost the AR signaling axis. However, their roles and utility as drug targets remain incompletely characterized.

The study shows an unexpected collaboration of FOXA1 and FOXA2 in mediating AR-independent cell proliferation in different lineage-plastic cancer subtypes. Conversely, joint loss-of-function or pharmacologic disruption of FOXA1 and FOXA2 leads to the collapse of lineage-specific oncogenic transcription factors followed by cell-cycle arrest. In summary, the findings uncover a druggable dependency for AR-positive and -negative prostate cancers.

Article:

Targeting FOXA1 and FOXA2 disrupts the lineage-specific oncogenic output program in prostate cancer. Nicola Formaggio, Jacopo Sgrignani, Gayathri Thillaiyampalam, Claudio Lorenzi, Giada A. Cassamagnago, Marco Coazzoli, Federico Costanzo, Yanick Uebelhart, Daniela Bossi, Diego Camuzi Cassiano, Andrea Rinaldi, Matteo Pecoraro, Roger Geiger, Raffaella Santoro, Marco Bolis, Andrea Cavalli, Jean-Philippe Theurrilat.