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Role of androgen receptor splice variant-7 (AR-V7) in prostate cancer resistance to 2nd-generation androgen receptor signaling inhibitors

Oncogene volume 39, pages 6935–6949 (2020)Cite this article

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A Correction to this article was published on 06 May 2021

A Correction to this article was published on 09 February 2021

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Abstract

The role of truncated androgen receptor splice variant-7 (AR-V7) in prostate cancer biology is an unresolved question. Is it simply a marker of resistance to 2nd-generation androgen receptor signaling inhibitors (ARSi) like abiraterone acetate (Abi) and enzalutamide (Enza) or a functional driver of lethal resistance via its ligand-independent transcriptional activity? To resolve this question, the correlation between resistance to ARSi and genetic chances and expression of full length AR (AR-FL) vs. AR-V7 were evaluated in a series of independent patient-derived xenografts (PDXs). While all PDXs lack PTEN expression, there is no consistent requirement for mutation in TP53, RB1, BRCA2, PIK3CA, or MSH2, or expression of SOX2 or ERG and ARSi resistance. Elevated expression of AR-FL alone is sufficient for Abi but not Enza resistance, even if AR-FL is gain-of-function (GOF) mutated. Enza resistance is consistently correlated with enhanced AR-V7 expression. In vitro and in vivo growth responses of Abi-/Enza-resistant LNCaP-95 cells in which CRISPR-Cas9 was used to knockout AR-FL or AR-V7 alone or in combination were evaluated. Combining these growth responses with RNAseq analysis demonstrates that both AR-FL- and AR-V7-dependent transcriptional complementation are needed for Abi/Enza resistance.

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Fig. 1: Characterization of CWR22-RH.
Fig. 2: RNA-seq-based expression analysis of a subset of genes across PDX models.
Fig. 3: Characterization of LvCaP-2 and LvCaP-2R.
Fig. 4: Characterization of SkCaP-1 and SkCaP-1R.
Fig. 5: Characterization of LNCaP variant under long-term ARSi-equivalent conditions (i.e., LN-95 cells).
Fig. 6: Characterization of AR-FL, AR-V7, vs. total AR knockout in LN-95 cells in vitro.
Fig. 7: Characterization of AR-FL, AR-V7, vs. total AR knockout in LN-95 cells in vivo.

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Acknowledgements

We are grateful to the patients and their families who participated in the Legacy Gift Rapid Autopsy program at Hopkins. We would like to acknowledge the Department of Defense Prostate Cancer Research Program W81XWH1810349 (JTI), W81XWH-17-1-0528 (WNB), W81XWH-18-2-0015 (AMM) and NIH Prostate SPOREs P50 CA058236 (JTI), Pathology Core from the Prostate SPORE P50 CA058236 (AMM) and P50 CA097186 (PSN), W81XWH-18-1-0347 (PSN), P01 CA163227 (PSN), Emerson Collective Cancer Research Fund [643396, (WNB)], Allegheny Health Network-Johns Hopkins University Cancer Research Fund (WNB), R01 CA185297 (JL and ESA). Also, we wish to thank the Cell Imaging Facility, Animal Core Facility, Tissue Histology Core, Genetic Resource Core, Cytogenetics Core Facility, and the Autopsy Core from the CCSG Grant supported by the SKCCC CCSG (P30 CA006973) for their services and assistance.

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Authors and Affiliations

  1. Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Yezi Zhu, Emmanuel S. Antonarakis, Angelo M. De Marzo, Alan K. Meeker, William B. Isaacs, Samuel R. Denmeade, Jun Luo, W. Nathaniel Brennen & John T. Isaacs

  2. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center (SKCCC), Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Susan L. Dalrymple, Emmanuel S. Antonarakis, Angelo M. De Marzo, Alan K. Meeker, William B. Isaacs, Samuel R. Denmeade, Jun Luo, W. Nathaniel Brennen & John T. Isaacs

  3. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA

    Ilsa Coleman & Peter S. Nelson

  4. Program for Personalized Cancer Care, North Shore University Health System, Evanston, IL, USA

    S. Lilly Zheng & Jianfeng Xu

  5. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Jody E. Hooper, Angelo M. De Marzo & Alan K. Meeker

  6. Department of Medicine and Urology, University of Washington, Seattle, WA, 98195, USA

    Peter S. Nelson

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Correspondence to John T. Isaacs.

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Conflict of interest

ESA is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Pfizer, Amgen, AstraZeneca, Bristol Myers Squibb, Bayer, Clovis, and Merck; has received research funding (to his institution) from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Bristol Myers Squibb, AstraZeneca, Clovis, and Merck. ESA and JL are co-inventors of an AR-V7 biomarker technology that has been licensed to Qiagen.

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Zhu, Y., Dalrymple, S.L., Coleman, I. et al. Role of androgen receptor splice variant-7 (AR-V7) in prostate cancer resistance to 2nd-generation androgen receptor signaling inhibitors. Oncogene 39, 6935–6949 (2020). https://doi.org/10.1038/s41388-020-01479-6

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