Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids

Gido Snaterse; Rosinda Mies; Wytske M. van Weerden; Pim J. French; Johan W. Jonker; Adriaan B. Houtsmuller; Martin E. van Royen; Jenny A. Visser; Johannes Hofland

doi:10.1038/s41391-022-00491-z

Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids

Gido Snaterse, Rosinda Mies, Wytske M. van Weerden, Pim J. French, Johan W. Jonker, Adriaan B. Houtsmuller, Martin E. van Royen, Jenny A. Visser, Johannes Hofland^*

^*Corresponding author for this work

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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 AR_L702H (3.4%), AR_H875Y (4.9%), and AR_T878A (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 AR_WT. The p.H875Y mutation selectively increased sensitivity of the AR for 11KT (EC50: 0.15 nmol/L, p < 0.05 vs AR_WT), whereas p.L702H decreased sensitivity for 11KT by almost 50-fold. While cortisol and prednisolone both stimulate AR_L702H, dexamethasone importantly does not.

Conclusion: Both testosterone and 11KT effectively contribute to AR_WT activation, while selective sensitization positions 11KT as a more prominent activator of AR_H875Y. Dexamethasone may be a suitable alternative to prednisolone and should be explored in patients bearing the AR_L702H.

Original language	English
Pages (from-to)	293-301
Number of pages	9
Journal	Prostate Cancer and Prostatic Diseases
Volume	26
Issue number	2
DOIs	https://doi.org/10.1038/s41391-022-00491-z
Publication status	Published - Jun 2023

Bibliographical note

Funding Information:
This study was funded by the Daniel den Hoed Foundation (investigator award to JH and funding support for the CTSF/Opera Phenix system) and by royalties from AMH assays paid to the Visser lab (JAV).

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

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10.1038/s41391-022-00491-z

s41391-022-00491-zFinal published version, 1.71 MBLicence: Unspecified

Cite this

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title = "Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids",

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.",

author = "Gido Snaterse and Rosinda Mies and {van Weerden}, {Wytske M.} and French, {Pim J.} and Jonker, {Johan W.} and Houtsmuller, {Adriaan B.} and {van Royen}, {Martin E.} and Visser, {Jenny A.} and Johannes Hofland",

note = "Funding Information: This study was funded by the Daniel den Hoed Foundation (investigator award to JH and funding support for the CTSF/Opera Phenix system) and by royalties from AMH assays paid to the Visser lab (JAV). Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = jun,

doi = "10.1038/s41391-022-00491-z",

language = "English",

volume = "26",

pages = "293--301",

journal = "Prostate Cancer and Prostatic Diseases",

issn = "1365-7852",

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T1 - Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids

AU - Snaterse, Gido

AU - Mies, Rosinda

AU - van Weerden, Wytske M.

AU - French, Pim J.

AU - Jonker, Johan W.

AU - Houtsmuller, Adriaan B.

AU - van Royen, Martin E.

AU - Visser, Jenny A.

AU - Hofland, Johannes

N1 - Funding Information: This study was funded by the Daniel den Hoed Foundation (investigator award to JH and funding support for the CTSF/Opera Phenix system) and by royalties from AMH assays paid to the Visser lab (JAV). Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2023/6

Y1 - 2023/6

N2 - 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.

AB - 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.

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Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids

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