Diverse AR gene rearrangements mediate resistance to androgen receptor inhibitors in metastatic prostate cancer

Yingming Li; Rendong Yang; Christine M. Henzler; Yeung Ho; Courtney Passow; Benjamin Auch; Suzanne Carreira; Daniel Nava Rodrigues; Claudia Bertan; Tae Hyun Hwang; David A. Quigley; Ha X. Dang; Colm Morrissey; Michael Fraser; Stephen R. Plymate; Christopher A. PlymateMaher; Felix Y. Feng; Johann S. De Bono; Scott M. Dehm

doi:10.1158/1078-0432.CCR-19-3023

Diverse AR gene rearrangements mediate resistance to androgen receptor inhibitors in metastatic prostate cancer

Yingming Li, Rendong Yang, Christine M. Henzler, Yeung Ho, Courtney Passow, Benjamin Auch, Suzanne Carreira, Daniel Nava Rodrigues, Claudia Bertan, Tae Hyun Hwang, David A. Quigley, Ha X. Dang, Colm Morrissey, Michael Fraser, Stephen R. Plymate, Christopher A. PlymateMaher, Felix Y. Feng, Johann S. De Bono, Scott M. Dehm

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

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Abstract

Purpose: Prostate cancer is the second leading cause of male cancer deaths. Castration-resistant prostate cancer (CRPC) is a lethal stage of the disease that emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. The purpose of this study was to identify genomic mechanisms that contribute to the development and progression of CRPC. Experimental Design: We used whole-genome and targeted DNA-sequencing approaches to identify mechanisms underlying CRPC in an aggregate cohort of 272 prostate cancer patients. We analyzed structural rearrangements at the genome-wide level and carried out a detailed structural rearrangement analysis of the AR locus. We used genome engineering to perform experimental modeling of AR gene rearrangements and long-read RNA sequencing to analyze effects on expression ofARandtruncatedARvariants (AR-V). Results: AR was among the most frequently rearranged genes in CRPC tumors. AR gene rearrangements promoted expression of diverse AR-V species. AR gene rearrangements occurring in the context of AR amplification correlated with AR overexpression. Cell lines with experimentally derived AR gene rearrangements displayed high expression of tumor-specific AR-Vs andwere resistant to endocrine therapies, including the AR antagonist enzalutamide. Conclusions: AR gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.

Original language	English (US)
Pages (from-to)	1965-1976
Number of pages	12
Journal	Clinical Cancer Research
Volume	26
Issue number	8
DOIs	https://doi.org/10.1158/1078-0432.CCR-19-3023
State	Published - Apr 15 2020

Bibliographical note

Funding Information:
This study was supported by the Movember Foundation/Prostate Cancer Foundation Challenge Award (S.M. Dehm), NIH R01CA174777 (S.M. Dehm), and U.S. Department of Defense Prostate Cancer Research Program Transformative Impact Award W81XWH-13-2-0093 (to S.R. Plymate and S.M. Dehm). The University of Washington Prostate Cancer Donor Rapid Autopsy Program was supported by the Department of Defense Prostate Cancer Biorepository Network (PCBN; W81XWH-14-2-0183), the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the PO1 NIH grant (PO1 CA163227), and the Institute for Prostate Cancer Research (IPCR). We thank the patients and their families. We acknowledge Celestia Higano, Evan Yu, Elahe Mostaghel, Heather Cheng, Pete Nelson, Bruce Montgomery, Mike Schweizer, Daniel Lin, Eva Corey, Funda Vakar-Lopez, Lawrence True, and the rapid autopsy teams for their contributions to the University of Washington Medical Center Prostate Cancer Donor Rapid Autopsy Program.

Publisher Copyright:
© 2020 American Association for Cancer Research.

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Li, Y., Yang, R., Henzler, C. M., Ho, Y., Passow, C., Auch, B., Carreira, S., Rodrigues, D. N., Bertan, C., Hwang, T. H., Quigley, D. A., Dang, H. X., Morrissey, C., Fraser, M., Plymate, S. R., PlymateMaher, C. A., Feng, F. Y., De Bono, J. S., & Dehm, S. M. (2020). Diverse AR gene rearrangements mediate resistance to androgen receptor inhibitors in metastatic prostate cancer. Clinical Cancer Research, 26(8), 1965-1976. https://doi.org/10.1158/1078-0432.CCR-19-3023

Li, Y , Yang, R , Henzler, CM, Ho, Y, Passow, C, Auch, B, Carreira, S, Rodrigues, DN, Bertan, C, Hwang, TH, Quigley, DA, Dang, HX, Morrissey, C, Fraser, M, Plymate, SR, PlymateMaher, CA, Feng, FY, De Bono, JS & Dehm, SM 2020, 'Diverse AR gene rearrangements mediate resistance to androgen receptor inhibitors in metastatic prostate cancer', Clinical Cancer Research, vol. 26, no. 8, pp. 1965-1976. https://doi.org/10.1158/1078-0432.CCR-19-3023

@article{b90b481aec224024bb1af275d63513df,

title = "Diverse AR gene rearrangements mediate resistance to androgen receptor inhibitors in metastatic prostate cancer",

abstract = "Purpose: Prostate cancer is the second leading cause of male cancer deaths. Castration-resistant prostate cancer (CRPC) is a lethal stage of the disease that emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. The purpose of this study was to identify genomic mechanisms that contribute to the development and progression of CRPC. Experimental Design: We used whole-genome and targeted DNA-sequencing approaches to identify mechanisms underlying CRPC in an aggregate cohort of 272 prostate cancer patients. We analyzed structural rearrangements at the genome-wide level and carried out a detailed structural rearrangement analysis of the AR locus. We used genome engineering to perform experimental modeling of AR gene rearrangements and long-read RNA sequencing to analyze effects on expression ofARandtruncatedARvariants (AR-V). Results: AR was among the most frequently rearranged genes in CRPC tumors. AR gene rearrangements promoted expression of diverse AR-V species. AR gene rearrangements occurring in the context of AR amplification correlated with AR overexpression. Cell lines with experimentally derived AR gene rearrangements displayed high expression of tumor-specific AR-Vs andwere resistant to endocrine therapies, including the AR antagonist enzalutamide. Conclusions: AR gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.",

author = "Yingming Li and Rendong Yang and Henzler, {Christine M.} and Yeung Ho and Courtney Passow and Benjamin Auch and Suzanne Carreira and Rodrigues, {Daniel Nava} and Claudia Bertan and Hwang, {Tae Hyun} and Quigley, {David A.} and Dang, {Ha X.} and Colm Morrissey and Michael Fraser and Plymate, {Stephen R.} and PlymateMaher, {Christopher A.} and Feng, {Felix Y.} and {De Bono}, {Johann S.} and Dehm, {Scott M.}",

note = "Funding Information: This study was supported by the Movember Foundation/Prostate Cancer Foundation Challenge Award (S.M. Dehm), NIH R01CA174777 (S.M. Dehm), and U.S. Department of Defense Prostate Cancer Research Program Transformative Impact Award W81XWH-13-2-0093 (to S.R. Plymate and S.M. Dehm). The University of Washington Prostate Cancer Donor Rapid Autopsy Program was supported by the Department of Defense Prostate Cancer Biorepository Network (PCBN; W81XWH-14-2-0183), the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the PO1 NIH grant (PO1 CA163227), and the Institute for Prostate Cancer Research (IPCR). We thank the patients and their families. We acknowledge Celestia Higano, Evan Yu, Elahe Mostaghel, Heather Cheng, Pete Nelson, Bruce Montgomery, Mike Schweizer, Daniel Lin, Eva Corey, Funda Vakar-Lopez, Lawrence True, and the rapid autopsy teams for their contributions to the University of Washington Medical Center Prostate Cancer Donor Rapid Autopsy Program. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

year = "2020",

month = apr,

day = "15",

doi = "10.1158/1078-0432.CCR-19-3023",

language = "English (US)",

volume = "26",

pages = "1965--1976",

journal = "Clinical Cancer Research",

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TY - JOUR

T1 - Diverse AR gene rearrangements mediate resistance to androgen receptor inhibitors in metastatic prostate cancer

AU - Li, Yingming

AU - Yang, Rendong

AU - Henzler, Christine M.

AU - Ho, Yeung

AU - Passow, Courtney

AU - Auch, Benjamin

AU - Carreira, Suzanne

AU - Rodrigues, Daniel Nava

AU - Bertan, Claudia

AU - Hwang, Tae Hyun

AU - Quigley, David A.

AU - Dang, Ha X.

AU - Morrissey, Colm

AU - Fraser, Michael

AU - Plymate, Stephen R.

AU - PlymateMaher, Christopher A.

AU - Feng, Felix Y.

AU - De Bono, Johann S.

AU - Dehm, Scott M.

N1 - Funding Information: This study was supported by the Movember Foundation/Prostate Cancer Foundation Challenge Award (S.M. Dehm), NIH R01CA174777 (S.M. Dehm), and U.S. Department of Defense Prostate Cancer Research Program Transformative Impact Award W81XWH-13-2-0093 (to S.R. Plymate and S.M. Dehm). The University of Washington Prostate Cancer Donor Rapid Autopsy Program was supported by the Department of Defense Prostate Cancer Biorepository Network (PCBN; W81XWH-14-2-0183), the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the PO1 NIH grant (PO1 CA163227), and the Institute for Prostate Cancer Research (IPCR). We thank the patients and their families. We acknowledge Celestia Higano, Evan Yu, Elahe Mostaghel, Heather Cheng, Pete Nelson, Bruce Montgomery, Mike Schweizer, Daniel Lin, Eva Corey, Funda Vakar-Lopez, Lawrence True, and the rapid autopsy teams for their contributions to the University of Washington Medical Center Prostate Cancer Donor Rapid Autopsy Program. Publisher Copyright: © 2020 American Association for Cancer Research.

PY - 2020/4/15

Y1 - 2020/4/15

N2 - Purpose: Prostate cancer is the second leading cause of male cancer deaths. Castration-resistant prostate cancer (CRPC) is a lethal stage of the disease that emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. The purpose of this study was to identify genomic mechanisms that contribute to the development and progression of CRPC. Experimental Design: We used whole-genome and targeted DNA-sequencing approaches to identify mechanisms underlying CRPC in an aggregate cohort of 272 prostate cancer patients. We analyzed structural rearrangements at the genome-wide level and carried out a detailed structural rearrangement analysis of the AR locus. We used genome engineering to perform experimental modeling of AR gene rearrangements and long-read RNA sequencing to analyze effects on expression ofARandtruncatedARvariants (AR-V). Results: AR was among the most frequently rearranged genes in CRPC tumors. AR gene rearrangements promoted expression of diverse AR-V species. AR gene rearrangements occurring in the context of AR amplification correlated with AR overexpression. Cell lines with experimentally derived AR gene rearrangements displayed high expression of tumor-specific AR-Vs andwere resistant to endocrine therapies, including the AR antagonist enzalutamide. Conclusions: AR gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.

AB - Purpose: Prostate cancer is the second leading cause of male cancer deaths. Castration-resistant prostate cancer (CRPC) is a lethal stage of the disease that emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. The purpose of this study was to identify genomic mechanisms that contribute to the development and progression of CRPC. Experimental Design: We used whole-genome and targeted DNA-sequencing approaches to identify mechanisms underlying CRPC in an aggregate cohort of 272 prostate cancer patients. We analyzed structural rearrangements at the genome-wide level and carried out a detailed structural rearrangement analysis of the AR locus. We used genome engineering to perform experimental modeling of AR gene rearrangements and long-read RNA sequencing to analyze effects on expression ofARandtruncatedARvariants (AR-V). Results: AR was among the most frequently rearranged genes in CRPC tumors. AR gene rearrangements promoted expression of diverse AR-V species. AR gene rearrangements occurring in the context of AR amplification correlated with AR overexpression. Cell lines with experimentally derived AR gene rearrangements displayed high expression of tumor-specific AR-Vs andwere resistant to endocrine therapies, including the AR antagonist enzalutamide. Conclusions: AR gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.

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DO - 10.1158/1078-0432.CCR-19-3023

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AN - SCOPUS:85083505244

SN - 1078-0432

VL - 26

SP - 1965

EP - 1976

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 8

ER -

Diverse AR gene rearrangements mediate resistance to androgen receptor inhibitors in metastatic prostate cancer

Abstract

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