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

Autor:	Chatterjee P; Division of Human Biology and., Schweizer MT; Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.; Department of Medicine, University of Washington, Seattle, Washington, USA., Lucas JM; Division of Human Biology and., Coleman I; Division of Human Biology and., Nyquist MD; Division of Human Biology and., Frank SB; Division of Human Biology and., Tharakan R; Division of Human Biology and., Mostaghel E; Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.; Department of Medicine, University of Washington, Seattle, Washington, USA., Luo J; Department of Urology, Johns Hopkins University, Baltimore, Maryland, USA., Pritchard CC; Department of Laboratory Medicine and., Lam HM; Department of Urology, University of Washington, Seattle, Washington, USA., Corey E; Department of Urology, University of Washington, Seattle, Washington, USA., Antonarakis ES; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA., Denmeade SR; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA., Nelson PS; Division of Human Biology and.; Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.; Department of Medicine, University of Washington, Seattle, Washington, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2019 Jul 16; Vol. 129 (10), pp. 4245-4260. Date of Electronic Publication: 2019 Jul 16.
DOI:	10.1172/JCI127613
Abstrakt:	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.
Databáze:	MEDLINE
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