TRIM24 Degradation Counteracts Adaptation to Androgen Receptor Inhibition in Prostate Cancer

Abstract The androgen receptor (AR) is the primary therapeutic target in prostate cancer. While androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSi) are effective, the disease eventually progresses to fatal castration-resistant prostate cancer (CRPC). That said, little is known about the mechanisms in residual disease that initiates tumor relapse upon ADT/ARSi. Here, we discover a crucial role for TRIM24 in supporting the survival of residual cell clusters primed for tumor relapse in vivo. Consequently, reducing TRIM24 with bifunctional degraders (dTRIM24) significantly delays or even prevents the emergence of CRPC in the context of AR reactivation and lineage plasticity. dTRIM24 not only inhibits AR signaling but also counteracts adaptive pathways engaged by AR inhibition itself, such as STAT3 activation and EMT. Our findings underscore the potential of TRIM24 as an effective and druggable target for preventing prostate cancer progression under AR inhibition. Significance Despite advances in targeting AR signaling in prostate cancer, tumor relapse remains a major concern. Here, we provide evidence that more durable responses can be achieved by pharmacologically degrading TRIM24. At the molecular level, TRIM24 degradation inhibits both AR signaling and adaptive pathways that enable tumor relapse. Competing Interest Statement J.P.T. and D.B. filed an Italian patent application (No. 10202400000504) relating to the manuscript's content, titled "Pharmacological degradation of TRIM24 inhibits castration-resistant prostate cancer growth and synergizes with hormonal therapy to prevent disease progression". J.P.T. has received funding for the venue of scientific conferences from Astellas, AstraZeneca, Pfizer, Janssen, Bayer, and Orion Pharma, and has received honoraria for consulting or advisory roles from Astellas. The other authors report no other disclosures related to the content of the manuscript.