Jenny A Visser1, Johannes Hofland2, Gido Snaterse1, Rosinda Mies1, Wytske M van Weerden3, Pim J French4, Johan W Jonker5, Adriaan B Houtsmuller6, Martin E van Royen6. 1. Department of Internal Medicine, Section of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. 2. Department of Internal Medicine, Section of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands. j.hofland@erasmusmc.nl. 3. Department of Urology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 4. Cancer Treatment Screening Facility, Department of Neurology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 5. Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 6. Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Abstract
BACKGROUND: Androgen receptor (AR) ligand-binding domain (LBD) mutations occur in ~20% of all castration-resistant prostate cancer (CRPC) patients. These mutations confer ligand promiscuity, but the affinity for many steroid hormone pathway intermediates is unknown. In this study, we investigated the stimulation of clinically relevant AR-LBD mutants by endogenous and exogenous steroid hormones present in CRPC patients to unravel their potential contribution to AR pathway reactivation. METHODS: A meta-analysis of studies reporting untargeted analysis of AR mutants was performed to identify clinically relevant AR-LBD mutations. Using luciferase reporter and quantitative fluorescent microscopy, these AR mutants were screened for sensitivity for various endogenous steroids and synthetic glucocorticoids used in the treatment of CRPC. RESULTS: The meta-analysis revealed that ARL702H (3.4%), ARH875Y (4.9%), and ART878A (4.4%) were the most prevalent AR-LBD mutations across 1614 CRPC patients from 21 unique studies. Testosterone (EC50: 0.22 nmol/L) and 11-ketotestosterone (11KT, EC50: 0.74 nmol/L) displayed subnanomolar affinity for ARWT. The p.H875Y mutation selectively increased sensitivity of the AR for 11KT (EC50: 0.15 nmol/L, p < 0.05 vs ARWT), whereas p.L702H decreased sensitivity for 11KT by almost 50-fold. While cortisol and prednisolone both stimulate ARL702H, dexamethasone importantly does not. CONCLUSION: Both testosterone and 11KT effectively contribute to ARWT activation, while selective sensitization positions 11KT as a more prominent activator of ARH875Y. Dexamethasone may be a suitable alternative to prednisolone and should be explored in patients bearing the ARL702H.
BACKGROUND: Androgen receptor (AR) ligand-binding domain (LBD) mutations occur in ~20% of all castration-resistant prostate cancer (CRPC) patients. These mutations confer ligand promiscuity, but the affinity for many steroid hormone pathway intermediates is unknown. In this study, we investigated the stimulation of clinically relevant AR-LBD mutants by endogenous and exogenous steroid hormones present in CRPC patients to unravel their potential contribution to AR pathway reactivation. METHODS: A meta-analysis of studies reporting untargeted analysis of AR mutants was performed to identify clinically relevant AR-LBD mutations. Using luciferase reporter and quantitative fluorescent microscopy, these AR mutants were screened for sensitivity for various endogenous steroids and synthetic glucocorticoids used in the treatment of CRPC. RESULTS: The meta-analysis revealed that ARL702H (3.4%), ARH875Y (4.9%), and ART878A (4.4%) were the most prevalent AR-LBD mutations across 1614 CRPC patients from 21 unique studies. Testosterone (EC50: 0.22 nmol/L) and 11-ketotestosterone (11KT, EC50: 0.74 nmol/L) displayed subnanomolar affinity for ARWT. The p.H875Y mutation selectively increased sensitivity of the AR for 11KT (EC50: 0.15 nmol/L, p < 0.05 vs ARWT), whereas p.L702H decreased sensitivity for 11KT by almost 50-fold. While cortisol and prednisolone both stimulate ARL702H, dexamethasone importantly does not. CONCLUSION: Both testosterone and 11KT effectively contribute to ARWT activation, while selective sensitization positions 11KT as a more prominent activator of ARH875Y. Dexamethasone may be a suitable alternative to prednisolone and should be explored in patients bearing the ARL702H.
Authors: Dennis J van de Wijngaart; Michel Molier; Scott J Lusher; Remko Hersmus; Guido Jenster; Jan Trapman; Hendrikus J Dubbink Journal: J Biol Chem Date: 2009-12-10 Impact factor: 5.157
Authors: Stefan Prekovic; Martin E van Royen; Arnout R D Voet; Bart Geverts; Rene Houtman; Diana Melchers; Kam Y J Zhang; Thomas Van den Broeck; Elien Smeets; Lien Spans; Adriaan B Houtsmuller; Steven Joniau; Frank Claessens; Christine Helsen Journal: Mol Cancer Ther Date: 2016-05-16 Impact factor: 6.261
Authors: James L Mohler; Christopher W Gregory; O Harris Ford; Desok Kim; Catharina M Weaver; Peter Petrusz; Elizabeth M Wilson; Frank S French Journal: Clin Cancer Res Date: 2004-01-15 Impact factor: 12.531
Authors: Himisha Beltran; Roman Yelensky; Garrett M Frampton; Kyung Park; Sean R Downing; Theresa Y MacDonald; Mirna Jarosz; Doron Lipson; Scott T Tagawa; David M Nanus; Philip J Stephens; Juan Miguel Mosquera; Maureen T Cronin; Mark A Rubin Journal: Eur Urol Date: 2012-09-05 Impact factor: 20.096
Authors: Michael Stanbrough; Glenn J Bubley; Kenneth Ross; Todd R Golub; Mark A Rubin; Trevor M Penning; Phillip G Febbo; Steven P Balk Journal: Cancer Res Date: 2006-03-01 Impact factor: 12.701
Authors: Charlie D Chen; Derek S Welsbie; Chris Tran; Sung Hee Baek; Randy Chen; Robert Vessella; Michael G Rosenfeld; Charles L Sawyers Journal: Nat Med Date: 2003-12-21 Impact factor: 53.440
Authors: Nada Lallous; Stanislav V Volik; Shannon Awrey; Eric Leblanc; Ronnie Tse; Josef Murillo; Kriti Singh; Arun A Azad; Alexander W Wyatt; Stephane LeBihan; Kim N Chi; Martin E Gleave; Paul S Rennie; Colin C Collins; Artem Cherkasov Journal: Genome Biol Date: 2016-01-26 Impact factor: 13.583