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. Eckloff; Jorge 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

doi:10.1158/1078-0432.CCR-17-0017

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

^*Corresponding author for this work

Urology

Research output: Contribution to journal › Article › peer-review

116 Scopus citations

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 language	English (US)
Pages (from-to)	4704-4715
Number of pages	12
Journal	Clinical Cancer Research
Volume	23
Issue number	16
DOIs	https://doi.org/10.1158/1078-0432.CCR-17-0017
State	Published - Aug 15 2017

Funding

We thank all patients who participated in this study for their selfless contribution in bringing precision medicine to future advanced prostate cancer patients. We appreciate the support of family members as well. We gratefully acknowledge the recruitment efforts of the following physicians who made patient referrals to the PROMOTE program: Sandeep Basu (Mayo Clinic Health Systems), Daniel Burns (Mayo Clinic Health Systems), Kevin Cockerill (Mayo Clinic Health Systems), Alan H. Bryce (Mayo Clinic, Arizona), Sarah Kratz (Mayo Clinic Health Systems), Mohammad Ranginwala (Mayo Clinic Health Systems), Amrit Singh (Mayo Clinic Health Systems), Gautam Jha (University of Minnesota), Badrinath Konety (University of Minnesota), Mir Ali Khan (CGH Medical Center), Ferdinand Addo (Prairie Lakes Healthcare System), Kevin Panico (Altru Health System), and Laura Joque (Essentia Health Brainerd Clinic). We also acknowledge the University of Wisconsin Carbone Cancer Center genitourinary clinical research group. Other contributing groups include the Mayo Clinic Cancer Center, the Pharmacogenomics Research Network (PGRN), A.T. Suharya and Ghan D.H., Joseph and Gail Gassner, Mayo Clinic Schulze Center for Novel Therapeutics in Cancer Research, and the Apogee Development of methodology: M. Kohli, Y. Ho, J.L. Van Etten, T. Hon, H. Sicotte, J. Jen, S.M. Dehm Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): M. Kohli, Y. Ho, J.M. Sperger, Y. Li, T. Hon, T. Clark, W. Tan, H. Sicotte, H. Thai, R. Jimenez, B.W. Eckloff, H.C. Pitot, B.A. Costello, J. Jen, E.D. Wieben, J.M. Lang, L. Wang Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): M. Kohli, D.W. Hillman, C. Henzler, R. Yang, J.M. Sperger, Y. Li, W. Tan, R.E. Carlson, L. Wang, H. Sicotte, H. Thai, P.T. Vedell, E.D. Wieben, J.M. Lang, S.M. Dehm Writing,review,and/orrevisionofthemanuscript:M.Kohli,Y.Ho,D.W.Hillman, E.Tseng, T.Clark,W.Tan,H.Sicotte,H.Thai,R.Jimenez,H.Huang,H.C.Pitot,B.A. Costello, J. Jen, E.D. Wieben, K.A.T. Silverstein, J.M. Lang, L. Wang, S.M. Dehm R. Jimenez is an employee of Histowiz. J.M. Lang has ownership interests (including patents) in Salus Discovery, LLC and is a consultant/advisory board member for Sanofi. S.M. Dehm is a consultant/advisory board member for Astellas/Medivation and Janssen Research and Development LLC. No potential conflicts of interest were disclosed by the other authors.

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General Medicine

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Kohli, M., Ho, Y., Hillman, D. W., Van Etten, J. L., Henzler, C., Yang, R., Sperger, J. M., Li, Y., Tseng, E., Hon, T., Clark, T., Tan, W., Carlson, R. E., Wang, L., Sicotte, H., Thai, H., Jimenez, R., Huang, H., Vedell, P. T., ... Dehm, S. M. (2017). Androgen receptor variant AR-V9 is coexpressed with AR-V7 in prostate cancer metastases and predicts abiraterone resistance. Clinical Cancer Research, 23(16), 4704-4715. https://doi.org/10.1158/1078-0432.CCR-17-0017

@article{6633ebb6029f49f58a846ab28f259425,

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.}",

note = "Publisher Copyright: {\textcopyright}2017 AACR.",

year = "2017",

month = aug,

day = "15",

doi = "10.1158/1078-0432.CCR-17-0017",

language = "English (US)",

volume = "23",

pages = "4704--4715",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "16",

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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

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

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

M3 - Article

C2 - 28473535

AN - SCOPUS:85028077218

SN - 1078-0432

VL - 23

SP - 4704

EP - 4715

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 16

ER -

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

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