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

Abstract

Prostate cancer (PC) is initially dependent on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with anti-tumor activity. SPA produced an AR-mediated, dose-dependent induction of DNA double-strand breaks (DSBs), G0/G1 cell cycle arrest and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA which was augmented by PARP1 inhibition. SPA-induced DSBs were accentuated in BRCA2-deficient PCs, and combining SPA with PARP or DNA-PKcs inhibition further repressed growth. Next-generation sequencing was performed on biospecimens from PC patients receiving SPA as part of ongoing Phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to PCs with AR amplification or DNA repair deficiency, and for combining SPA therapy with PARP inhibition.

• Authors: Payel Chatterjee, Michael T Schweizer, Jared M Lucas, Ilsa Coleman, Michael D Nyquist, Sander B Frank, Robin Tharakan, Elahe Mostaghel, Jun Luo, Colin C Pritchard, Hung-Ming Lam, Eva Corey, Emmanuel S Antonarakis, Samuel R Denmeade, Peter S Nelson
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 129 Issue 10 Pg. 4245-4260 (07 16 2019) ISSN: 1558-8238 [Electronic] United States
• PMID: 31310591 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Androgens
• BRCA2 Protein
• BRCA2 protein, human
• Receptors, Androgen
• Poly(ADP-ribose) Polymerases

Topics

• Androgens (pharmacology)
• BRCA2 Protein (deficiency, metabolism)
• Cellular Senescence (drug effects, genetics)
• DNA Damage
• G1 Phase Cell Cycle Checkpoints (drug effects, genetics)
• Gene Amplification
• Humans
• Male
• PC-3 Cells
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Receptors, Androgen (genetics, metabolism)
• Resting Phase, Cell Cycle (drug effects, genetics)