Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids
© 2022. The Author(s), under exclusive licence to Springer Nature Limited..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:26 |
|---|---|
| Enthalten in: |
Prostate cancer and prostatic diseases - 26(2023), 2 vom: 19. Juni, Seite 293-301 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Snaterse, Gido [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
3XMK78S47O |
|---|
| Anmerkungen: |
Date Completed 09.06.2023 Date Revised 14.06.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41391-022-00491-z |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM335812414 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM335812414 | ||
| 003 | DE-627 | ||
| 005 | 20231225230718.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41391-022-00491-z |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1119.xml |
| 035 | |a (DE-627)NLM335812414 | ||
| 035 | |a (NLM)35046557 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Snaterse, Gido |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Androgen receptor mutations modulate activation by 11-oxygenated androgens and glucocorticoids |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 09.06.2023 | ||
| 500 | |a Date Revised 14.06.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s), under exclusive licence to Springer Nature Limited. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Meta-Analysis | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Androgens |2 NLM | |
| 650 | 7 | |a Receptors, Androgen |2 NLM | |
| 650 | 7 | |a Glucocorticoids |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Testosterone |2 NLM | |
| 650 | 7 | |a 3XMK78S47O |2 NLM | |
| 650 | 7 | |a Steroids |2 NLM | |
| 650 | 7 | |a Prednisolone |2 NLM | |
| 650 | 7 | |a 9PHQ9Y1OLM |2 NLM | |
| 650 | 7 | |a Dexamethasone |2 NLM | |
| 650 | 7 | |a 7S5I7G3JQL |2 NLM | |
| 700 | 1 | |a Mies, Rosinda |e verfasserin |4 aut | |
| 700 | 1 | |a van Weerden, Wytske M |e verfasserin |4 aut | |
| 700 | 1 | |a French, Pim J |e verfasserin |4 aut | |
| 700 | 1 | |a Jonker, Johan W |e verfasserin |4 aut | |
| 700 | 1 | |a Houtsmuller, Adriaan B |e verfasserin |4 aut | |
| 700 | 1 | |a van Royen, Martin E |e verfasserin |4 aut | |
| 700 | 1 | |a Visser, Jenny A |e verfasserin |4 aut | |
| 700 | 1 | |a Hofland, Johannes |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Prostate cancer and prostatic diseases |d 1997 |g 26(2023), 2 vom: 19. Juni, Seite 293-301 |w (DE-627)NLM097536202 |x 1476-5608 |7 nnns |
| 773 | 1 | 8 | |g volume:26 |g year:2023 |g number:2 |g day:19 |g month:06 |g pages:293-301 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41391-022-00491-z |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 26 |j 2023 |e 2 |b 19 |c 06 |h 293-301 | ||