Androgen receptor variant AR-V9 is coexpressed with AR-V7 in prostate cancer metastases and predicts abiraterone resistance

Manish Kohli, Yeung Ho, David W. Hillman, Jamie L. Van Etten, Christine Henzler, Rendong Yang, Jamie M. Sperger, Yingming Li, Elizabeth Tseng, Ting Hon, Tyson Clark, Winston Tan, Rachel E. Carlson, Liguo Wang, Hugues Sicotte, Ho Thai, Rafael Jimenez, Haojie Huang, Peter T. Vedell, Bruce W. EckloffJorge F. Quevedo, Henry C. Pitot, Brian A. Costello, Jin Jen, Eric D. Wieben, Kevin A.T. Silverstein, Joshua M. Lang, Liewei Wang, Scott M. Dehm

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Abstract

Purpose: Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be coexpressed with AR-V7 and promote resistance to AR-targeted therapies. Experimental Design: We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Coexpression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate. Results: AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 30 terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR ¼ 4.0; 95% confidence interval, 1.31–12.2; P ¼ 0.02). Conclusions: AR-V9 may be an important component of therapeutic resistance in CRPC.

Original languageEnglish (US)
Pages (from-to)4704-4715
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number16
DOIs
StatePublished - Aug 15 2017

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Androgen Receptors
Prostatic Neoplasms
Neoplasm Metastasis
Castration
abiraterone
Messenger RNA
Ligands
RNA Isoforms
Circulating Neoplastic Cells

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Androgen receptor variant AR-V9 is coexpressed with AR-V7 in prostate cancer metastases and predicts abiraterone resistance. / Kohli, Manish; Ho, Yeung; Hillman, David W.; Van Etten, Jamie L.; Henzler, Christine; Yang, Rendong; Sperger, Jamie M.; Li, Yingming; Tseng, Elizabeth; Hon, Ting; Clark, Tyson; Tan, Winston; Carlson, Rachel E.; Wang, Liguo; Sicotte, Hugues; Thai, Ho; Jimenez, Rafael; Huang, Haojie; Vedell, Peter T.; Eckloff, Bruce W.; Quevedo, Jorge F.; Pitot, Henry C.; Costello, Brian A.; Jen, Jin; Wieben, Eric D.; Silverstein, Kevin A.T.; Lang, Joshua M.; Wang, Liewei; Dehm, Scott M.

In: Clinical Cancer Research, Vol. 23, No. 16, 15.08.2017, p. 4704-4715.

Research output: Contribution to journalArticle

Kohli, M, Ho, Y, Hillman, DW, Van Etten, JL, Henzler, C, Yang, R, Sperger, JM, Li, Y, Tseng, E, Hon, T, Clark, T, Tan, W, Carlson, RE, Wang, L, Sicotte, H, Thai, H, Jimenez, R, Huang, H, Vedell, PT, Eckloff, BW, Quevedo, JF, Pitot, HC, Costello, BA, Jen, J, Wieben, ED, Silverstein, KAT, Lang, JM, Wang, L & Dehm, SM 2017, 'Androgen receptor variant AR-V9 is coexpressed with AR-V7 in prostate cancer metastases and predicts abiraterone resistance', Clinical Cancer Research, vol. 23, no. 16, pp. 4704-4715. https://doi.org/10.1158/1078-0432.CCR-17-0017
Kohli, Manish ; Ho, Yeung ; Hillman, David W. ; Van Etten, Jamie L. ; Henzler, Christine ; Yang, Rendong ; Sperger, Jamie M. ; Li, Yingming ; Tseng, Elizabeth ; Hon, Ting ; Clark, Tyson ; Tan, Winston ; Carlson, Rachel E. ; Wang, Liguo ; Sicotte, Hugues ; Thai, Ho ; Jimenez, Rafael ; Huang, Haojie ; Vedell, Peter T. ; Eckloff, Bruce W. ; Quevedo, Jorge F. ; Pitot, Henry C. ; Costello, Brian A. ; Jen, Jin ; Wieben, Eric D. ; Silverstein, Kevin A.T. ; Lang, Joshua M. ; Wang, Liewei ; Dehm, Scott M. / Androgen receptor variant AR-V9 is coexpressed with AR-V7 in prostate cancer metastases and predicts abiraterone resistance. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 16. pp. 4704-4715.
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title = "Androgen receptor variant AR-V9 is coexpressed with AR-V7 in prostate cancer metastases and predicts abiraterone resistance",
abstract = "Purpose: Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be coexpressed with AR-V7 and promote resistance to AR-targeted therapies. Experimental Design: We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Coexpression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate. Results: AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 30 terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR ¼ 4.0; 95{\%} confidence interval, 1.31–12.2; P ¼ 0.02). Conclusions: AR-V9 may be an important component of therapeutic resistance in CRPC.",
author = "Manish Kohli and Yeung Ho and Hillman, {David W.} and {Van Etten}, {Jamie L.} and Christine Henzler and Rendong Yang and Sperger, {Jamie M.} and Yingming Li and Elizabeth Tseng and Ting Hon and Tyson Clark and Winston Tan and Carlson, {Rachel E.} and Liguo Wang and Hugues Sicotte and Ho Thai and Rafael Jimenez and Haojie Huang and Vedell, {Peter T.} and Eckloff, {Bruce W.} and Quevedo, {Jorge F.} and Pitot, {Henry C.} and Costello, {Brian A.} and Jin Jen and Wieben, {Eric D.} and Silverstein, {Kevin A.T.} and Lang, {Joshua M.} and Liewei Wang and Dehm, {Scott M.}",
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TY - JOUR

T1 - Androgen receptor variant AR-V9 is coexpressed with AR-V7 in prostate cancer metastases and predicts abiraterone resistance

AU - Kohli, Manish

AU - Ho, Yeung

AU - Hillman, David W.

AU - Van Etten, Jamie L.

AU - Henzler, Christine

AU - Yang, Rendong

AU - Sperger, Jamie M.

AU - Li, Yingming

AU - Tseng, Elizabeth

AU - Hon, Ting

AU - Clark, Tyson

AU - Tan, Winston

AU - Carlson, Rachel E.

AU - Wang, Liguo

AU - Sicotte, Hugues

AU - Thai, Ho

AU - Jimenez, Rafael

AU - Huang, Haojie

AU - Vedell, Peter T.

AU - Eckloff, Bruce W.

AU - Quevedo, Jorge F.

AU - Pitot, Henry C.

AU - Costello, Brian A.

AU - Jen, Jin

AU - Wieben, Eric D.

AU - Silverstein, Kevin A.T.

AU - Lang, Joshua M.

AU - Wang, Liewei

AU - Dehm, Scott M.

PY - 2017/8/15

Y1 - 2017/8/15

N2 - Purpose: Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be coexpressed with AR-V7 and promote resistance to AR-targeted therapies. Experimental Design: We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Coexpression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate. Results: AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 30 terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR ¼ 4.0; 95% confidence interval, 1.31–12.2; P ¼ 0.02). Conclusions: AR-V9 may be an important component of therapeutic resistance in CRPC.

AB - Purpose: Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be coexpressed with AR-V7 and promote resistance to AR-targeted therapies. Experimental Design: We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Coexpression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate. Results: AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 30 terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR ¼ 4.0; 95% confidence interval, 1.31–12.2; P ¼ 0.02). Conclusions: AR-V9 may be an important component of therapeutic resistance in CRPC.

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U2 - 10.1158/1078-0432.CCR-17-0017

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