Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Prostate cancer (PC) growth is initially driven by androgen receptor (AR) signaling.
• Current therapies target AR activity, but supraphysiological androgen (SPA) can paradoxically inhibit PC growth.
• Understanding the mechanisms behind SPA's anti-tumor effects is crucial for developing new therapeutic strategies.

Purpose of the Study:

• To elucidate the mechanisms by which SPA inhibits PC growth.
• To identify molecular contexts that associate with SPA's anti-tumor activity.
• To explore potential combination therapies involving SPA.

Main Methods:

• Investigated SPA's effects on AR signaling, DNA double-strand breaks (DSBs), cell cycle arrest, and senescence in PC cells.
• Assessed the impact of SPA on DNA repair gene expression and DNA damage restoration.
• Utilized next-generation sequencing on patient biospecimens from Phase II clinical trials of SPA therapy.

Main Results:

• SPA induced AR-mediated, dose-dependent DSBs, G0/G1 cell cycle arrest, and senescence.
• SPA repressed DNA repair genes and delayed DNA damage restoration, an effect potentiated by PARP1 inhibition.
• SPA-induced DSBs were amplified in BRCA2-deficient PCs, and combination therapy with PARP or DNA-PKcs inhibitors repressed growth.
• Patients with mutations in homology-directed DNA repair genes showed better clinical responses to SPA.

Conclusions:

• SPA induces DNA damage and cell cycle arrest, leading to PC growth inhibition.
• Molecular context, particularly DNA repair deficiencies, influences response to SPA therapy.
• SPA therapy could be directed towards PCs with AR amplification or DNA repair defects, potentially combined with PARP inhibitors.