Targeting FOXA1 and FOXA2 disrupts the oncogenic output program in prostate cancer
Institute of Oncology Research
Researchers from the Institute of Oncology Research (IOR) and the Institute for Research in Biomedicine (IRB) have developed the first inhibitors targeting FOXA1 and FOXA2, transcription factors long deemed “undruggable” and key drivers of prostate cancer. Published in Cell Reports, the study — led by Prof. Jean-Philippe Theurillat (IOR) and Prof. Andrea Cavalli (IRB) — opens new therapeutic avenues for both androgen receptor (AR)-positive and AR-negative prostate cancers.
Activation of the androgen receptor (AR) represents the main oncogenic pathway and therapeutic target in prostate cancer. The pioneer transcription factor FOXA1 enables AR signaling, while its homolog FOXA2 is expressed in advanced, lineage-plastic prostate cancers that have lost AR dependence.
In this study, the researchers uncovered an unexpected collaboration between FOXA1 and FOXA2 in sustaining AR-independent cell proliferation across distinct prostate cancer subtypes. Remarkably, simultaneous genetic or pharmacological inhibition of both factors causes a collapse of lineage-specific oncogenic transcription programs, resulting in cell-cycle arrest.
These findings reveal a previously unknown vulnerability and define FOXA1 and FOXA2 as druggable targets in both AR-positive and AR-negative prostate cancers.
The study: https://www.sciencedirect.com/science/article/pii/S2211124725010952?via%3Dihub
