Deletion of Zbtb7a or Trp53 promotes CRPC and is associated with deregulation of XAF1 and SRD5A1.
Major finding: Deletion of Zbtb7a or Trp53 promotes CRPC and is associated with deregulation of XAF1 and SRD5A1.
Approach: Integrated analysis of mouse and human tumors identified mechanisms of castration resistance.
Impact: Combined inhibition of XIAP and SRD5A1 enhances sensitivity to androgen deprivation therapy.
Androgen deprivation therapy (ADT) is the standard of care for men with prostate cancer and is initially effective in reducing tumor growth. However, castration-resistant prostate cancer (CRPC) inevitably develops in most patients, underscoring the need to identify combinatorial therapeutic strategies. To identify mechanisms underlying the development of CRPC, Lunardi and colleagues analyzed a Pten loss–driven mouse model of prostate cancer and human prostate cancer samples using an integrated coclinical approach. Mice with prostate-specific Pten deletion initially responded to castration with a reduction in tumor volume but rapidly acquired resistance to ADT. In contrast, concomitant deletion of Trp53 or zinc finger and BTB domain-containing 7A (Zbtb7a), which was recently characterized as a tumor suppressor in the prostate, conferred resistance to ADT; this effect was mediated via sustained androgen-independent proliferation, inhibition of apoptosis, and increased nuclear localization of androgen receptor in tumors following castration. In addition, loss of TP53 and ZBTB7A was associated with poor response to ADT and metastatic CRPC in patient samples. Castration-resistant murine prostate tumors were characterized by diminished expression of the proapoptotic protein X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1), a negative regulator of XIAP, and upregulation of steroid-5-alpha-reductase, alpha polypeptide 1 (SRD5A1), an enzyme that converts testosterone to dihydrotestosterone. Similar deregulation of XAF1 and SRD5A1 was also detected in aggressive human prostate tumors with poor sensitivity to ADT, suggesting that these proteins may be biomarkers of castration resistance. Furthermore, treatment of castration-resistant tumors with the XIAP inhibitor embelin sensitized these tumors to ADT, whereas the triple combination of embelin, ADT, and the SRD5A1 inhibitor dutasteride enhanced apoptosis and further reduced castration-resistant tumor growth. These results demonstrate the utility of the coclinical approach to identify actionable targets and suggest a therapeutic strategy to overcome castration resistance.