Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer

Adam Sharp, Ilsa Coleman, Wei Yuan, Cynthia Sprenger, David Dolling, Daniel Nava Rodrigues, Joshua W. Russo, Ines Figueiredo, Claudia Bertan, George Seed, Ruth Riisnaes, Takuma Uo, Antje Neeb, Jonathan Welti, Colm Morrissey, Suzanne Carreira, Jun Luo, Peter S. Nelson, Steven P. Balk, Lawrence D. TrueJohann S. De Bono, Stephen R. Plymate

Research output: Contribution to journalArticle

Abstract

BACKGROUND. Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival from endocrine therapies in castration-resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 expression in prostate cancer (PC) tissue. METHODS. Following generation and validation of a potentially novel AR-V7 antibody for IHC, AR-V7 protein expression was determined for 358 primary prostate samples and 293 metastatic biopsies. Associations with disease progression, fulllength androgen receptor (AR-FL) expression, response to therapy, and gene expression were determined. RESULTS. We demonstrated that AR-V7 protein is rarely expressed (<1%) in primary PC but is frequently detected (75% of cases) following androgen deprivation therapy, with further significant (P = 0.020) increase in expression following abiraterone acetate or enzalutamide therapy. In CRPC, AR-V7 expression is predominantly (94% of cases) nuclear and correlates with AR-FL expression (P ≤ 0.001) and AR copy number (P = 0.026). However, dissociation of expression was observed, suggesting that mRNA splicing remains crucial for AR-V7 generation. AR-V7 expression was heterogeneous between different metastases from a patient, although AR-V7 expression was similar within a metastasis. Moreover, AR-V7 expression correlated with a unique 59-gene signature in CRPC, including HOXB13, a critical coregulator of ARV7 function. Finally, AR-V7-negative disease associated with better prostate-specific antigen (PSA) responses (100% vs. 54%, P = 0.03) and overall survival (74.3 vs. 25.2 months, hazard ratio 0.23 [0.07-0.79], P = 0.02) from endocrine therapies (pre-chemotherapy). CONCLUSION. This study provides impetus to develop therapies that abrogate AR-V7 signaling to improve our understanding of AR-V7 biology and to confirm the clinical significance of AR-V7.

Original languageEnglish (US)
Article numberCI122819
JournalJournal of Clinical Investigation
Volume129
Issue number1
DOIs
StatePublished - Jan 2 2019

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Castration
Androgen Receptors
Prostatic Neoplasms
Protein Isoforms
Therapeutics
Neoplasm Metastasis
Biopsy
Survival
Prostate-Specific Antigen
Androgens
Disease Progression
Prostate

ASJC Scopus subject areas

  • Medicine(all)

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Sharp, A., Coleman, I., Yuan, W., Sprenger, C., Dolling, D., Rodrigues, D. N., ... Plymate, S. R. (2019). Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. Journal of Clinical Investigation, 129(1), [CI122819]. https://doi.org/10.1172/JCI122819

Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. / Sharp, Adam; Coleman, Ilsa; Yuan, Wei; Sprenger, Cynthia; Dolling, David; Rodrigues, Daniel Nava; Russo, Joshua W.; Figueiredo, Ines; Bertan, Claudia; Seed, George; Riisnaes, Ruth; Uo, Takuma; Neeb, Antje; Welti, Jonathan; Morrissey, Colm; Carreira, Suzanne; Luo, Jun; Nelson, Peter S.; Balk, Steven P.; True, Lawrence D.; De Bono, Johann S.; Plymate, Stephen R.

In: Journal of Clinical Investigation, Vol. 129, No. 1, CI122819, 02.01.2019.

Research output: Contribution to journalArticle

Sharp, A, Coleman, I, Yuan, W, Sprenger, C, Dolling, D, Rodrigues, DN, Russo, JW, Figueiredo, I, Bertan, C, Seed, G, Riisnaes, R, Uo, T, Neeb, A, Welti, J, Morrissey, C, Carreira, S, Luo, J, Nelson, PS, Balk, SP, True, LD, De Bono, JS & Plymate, SR 2019, 'Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer', Journal of Clinical Investigation, vol. 129, no. 1, CI122819. https://doi.org/10.1172/JCI122819
Sharp, Adam ; Coleman, Ilsa ; Yuan, Wei ; Sprenger, Cynthia ; Dolling, David ; Rodrigues, Daniel Nava ; Russo, Joshua W. ; Figueiredo, Ines ; Bertan, Claudia ; Seed, George ; Riisnaes, Ruth ; Uo, Takuma ; Neeb, Antje ; Welti, Jonathan ; Morrissey, Colm ; Carreira, Suzanne ; Luo, Jun ; Nelson, Peter S. ; Balk, Steven P. ; True, Lawrence D. ; De Bono, Johann S. ; Plymate, Stephen R. / Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 1.
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abstract = "BACKGROUND. Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival from endocrine therapies in castration-resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 expression in prostate cancer (PC) tissue. METHODS. Following generation and validation of a potentially novel AR-V7 antibody for IHC, AR-V7 protein expression was determined for 358 primary prostate samples and 293 metastatic biopsies. Associations with disease progression, fulllength androgen receptor (AR-FL) expression, response to therapy, and gene expression were determined. RESULTS. We demonstrated that AR-V7 protein is rarely expressed (<1{\%}) in primary PC but is frequently detected (75{\%} of cases) following androgen deprivation therapy, with further significant (P = 0.020) increase in expression following abiraterone acetate or enzalutamide therapy. In CRPC, AR-V7 expression is predominantly (94{\%} of cases) nuclear and correlates with AR-FL expression (P ≤ 0.001) and AR copy number (P = 0.026). However, dissociation of expression was observed, suggesting that mRNA splicing remains crucial for AR-V7 generation. AR-V7 expression was heterogeneous between different metastases from a patient, although AR-V7 expression was similar within a metastasis. Moreover, AR-V7 expression correlated with a unique 59-gene signature in CRPC, including HOXB13, a critical coregulator of ARV7 function. Finally, AR-V7-negative disease associated with better prostate-specific antigen (PSA) responses (100{\%} vs. 54{\%}, P = 0.03) and overall survival (74.3 vs. 25.2 months, hazard ratio 0.23 [0.07-0.79], P = 0.02) from endocrine therapies (pre-chemotherapy). CONCLUSION. This study provides impetus to develop therapies that abrogate AR-V7 signaling to improve our understanding of AR-V7 biology and to confirm the clinical significance of AR-V7.",
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T1 - Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer

AU - Sharp, Adam

AU - Coleman, Ilsa

AU - Yuan, Wei

AU - Sprenger, Cynthia

AU - Dolling, David

AU - Rodrigues, Daniel Nava

AU - Russo, Joshua W.

AU - Figueiredo, Ines

AU - Bertan, Claudia

AU - Seed, George

AU - Riisnaes, Ruth

AU - Uo, Takuma

AU - Neeb, Antje

AU - Welti, Jonathan

AU - Morrissey, Colm

AU - Carreira, Suzanne

AU - Luo, Jun

AU - Nelson, Peter S.

AU - Balk, Steven P.

AU - True, Lawrence D.

AU - De Bono, Johann S.

AU - Plymate, Stephen R.

PY - 2019/1/2

Y1 - 2019/1/2

N2 - BACKGROUND. Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival from endocrine therapies in castration-resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 expression in prostate cancer (PC) tissue. METHODS. Following generation and validation of a potentially novel AR-V7 antibody for IHC, AR-V7 protein expression was determined for 358 primary prostate samples and 293 metastatic biopsies. Associations with disease progression, fulllength androgen receptor (AR-FL) expression, response to therapy, and gene expression were determined. RESULTS. We demonstrated that AR-V7 protein is rarely expressed (<1%) in primary PC but is frequently detected (75% of cases) following androgen deprivation therapy, with further significant (P = 0.020) increase in expression following abiraterone acetate or enzalutamide therapy. In CRPC, AR-V7 expression is predominantly (94% of cases) nuclear and correlates with AR-FL expression (P ≤ 0.001) and AR copy number (P = 0.026). However, dissociation of expression was observed, suggesting that mRNA splicing remains crucial for AR-V7 generation. AR-V7 expression was heterogeneous between different metastases from a patient, although AR-V7 expression was similar within a metastasis. Moreover, AR-V7 expression correlated with a unique 59-gene signature in CRPC, including HOXB13, a critical coregulator of ARV7 function. Finally, AR-V7-negative disease associated with better prostate-specific antigen (PSA) responses (100% vs. 54%, P = 0.03) and overall survival (74.3 vs. 25.2 months, hazard ratio 0.23 [0.07-0.79], P = 0.02) from endocrine therapies (pre-chemotherapy). CONCLUSION. This study provides impetus to develop therapies that abrogate AR-V7 signaling to improve our understanding of AR-V7 biology and to confirm the clinical significance of AR-V7.

AB - BACKGROUND. Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival from endocrine therapies in castration-resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 expression in prostate cancer (PC) tissue. METHODS. Following generation and validation of a potentially novel AR-V7 antibody for IHC, AR-V7 protein expression was determined for 358 primary prostate samples and 293 metastatic biopsies. Associations with disease progression, fulllength androgen receptor (AR-FL) expression, response to therapy, and gene expression were determined. RESULTS. We demonstrated that AR-V7 protein is rarely expressed (<1%) in primary PC but is frequently detected (75% of cases) following androgen deprivation therapy, with further significant (P = 0.020) increase in expression following abiraterone acetate or enzalutamide therapy. In CRPC, AR-V7 expression is predominantly (94% of cases) nuclear and correlates with AR-FL expression (P ≤ 0.001) and AR copy number (P = 0.026). However, dissociation of expression was observed, suggesting that mRNA splicing remains crucial for AR-V7 generation. AR-V7 expression was heterogeneous between different metastases from a patient, although AR-V7 expression was similar within a metastasis. Moreover, AR-V7 expression correlated with a unique 59-gene signature in CRPC, including HOXB13, a critical coregulator of ARV7 function. Finally, AR-V7-negative disease associated with better prostate-specific antigen (PSA) responses (100% vs. 54%, P = 0.03) and overall survival (74.3 vs. 25.2 months, hazard ratio 0.23 [0.07-0.79], P = 0.02) from endocrine therapies (pre-chemotherapy). CONCLUSION. This study provides impetus to develop therapies that abrogate AR-V7 signaling to improve our understanding of AR-V7 biology and to confirm the clinical significance of AR-V7.

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