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Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer

  1. Laura Cato
  2. Antje Neeb
  3. Adam Sharp
  4. Victor Buzón
  5. Scott B Ficarro
  6. Linxiao Yang
  7. Claudia Muhle-Goll
  8. Nane C Kuznik
  9. Ruth Riisnaes
  10. Daniel Nava Rodrigues
  11. Olivier Armant
  12. Victor Gourain
  13. Guillaume Adelmant
  14. Emmanuel A Ntim
  15. Thomas Westerling
  16. David Dolling
  17. Pasquale Rescigno
  18. Ines Figueiredo
  19. Friedrich Fauser
  20. Jennifer Wu
  21. Jaice T Rottenberg
  22. Liubov Shatkina
  23. Claudia Ester
  24. Burkhard Luy
  25. Holger Puchta
  26. Jakob Troppmair
  27. Nicole Jung
  28. Stefan Bräse
  29. Uwe Strähle
  30. Jarrod A Marto
  31. Gerd Ulrich Nienhaus
  32. Bissan Al-Lazikani
  33. Xavier Salvatella
  34. Johann S de Bono
  35. Andrew CB Cato Is a corresponding author
  36. Myles Brown Is a corresponding author
  1. Dana-Farber Cancer Institute, United States
  2. Institute of Cancer Research, United Kingdom
  3. The Barcelona Institute of Science and Technology, Spain
  4. Karlsruhe Institute of Technology, Germany
  5. Innsbruck Medical University, Austria
  6. The Institute of Cancer Research, United Kingdom
  7. Dana-Farber Cancer Instittue, United States
Research Article
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Cite as: eLife 2017;6:e27159 doi: 10.7554/eLife.27159

Abstract

Targeting the activation function-1 (AF-1) domain located in the N-terminus of the androgen receptor (AR) is an attractive therapeutic alternative to the current approaches to inhibit AR action in prostate cancer (PCa). Here we show that the AR AF-1 is bound by the cochaperone Bag-1L. Mutations in the AR interaction domain or loss of Bag-1L abrogate AR signaling and reduce PCa growth. Clinically, Bag-1L protein levels increase with progression to castration-resistant PCa (CRPC) and high levels of Bag-1L in primary PCa associate with a reduced clinical benefit from abiraterone when these tumors progress. Intriguingly, residues in Bag-1L important for its interaction with the AR AF-1 are within a potentially druggable pocket, implicating Bag-1L as a potential therapeutic target in PCa.

Article and author information

Author details

  1. Laura Cato

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-7072-4368
  2. Antje Neeb

    Prostate Cancer Target Therapy Group, Institute of Cancer Research, Sutton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Adam Sharp

    Prostate Cancer Target Therapy Group, Institute of Cancer Research, Sutton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Victor Buzón

    Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  5. Scott B Ficarro

    Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Linxiao Yang

    Institute of Applied Physics, Karlsruhe Institute of Technology, Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Claudia Muhle-Goll

    Institute for Biological Interfaces 4, Karlsruhe Institute of Technology, Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Nane C Kuznik

    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Ruth Riisnaes

    Prostate Cancer Target Therapy Group, Institute of Cancer Research, Sutton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Daniel Nava Rodrigues

    Prostate Cancer Target Therapy Group, Institute of Cancer Research, Sutton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Olivier Armant

    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Victor Gourain

    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Guillaume Adelmant

    The Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Emmanuel A Ntim

    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Thomas Westerling

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. David Dolling

    Clinical Trials and Statistics Unit, Institute of Cancer Research, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  17. Pasquale Rescigno

    Prostate Cancer Target Therapy Group, Institute of Cancer Research, Sutton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  18. Ines Figueiredo

    Prostate Cancer Target Therapy Group, Institute of Cancer Research, Sutton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  19. Friedrich Fauser

    Botanical Institute II, Karlsruhe Institute of Technology, Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
  20. Jennifer Wu

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Jaice T Rottenberg

    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Liubov Shatkina

    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  23. Claudia Ester

    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  24. Burkhard Luy

    Institute for Biological Interfaces 4, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  25. Holger Puchta

    Botanical Institute II, Karlsruhe Institute of Technology, Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
  26. Jakob Troppmair

    Daniel-Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
    Competing interests
    The authors declare that no competing interests exist.
  27. Nicole Jung

    Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
  28. Stefan Bräse

    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  29. Uwe Strähle

    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  30. Jarrod A Marto

    The Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  31. Gerd Ulrich Nienhaus

    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-5027-3192
  32. Bissan Al-Lazikani

    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  33. Xavier Salvatella

    Institute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-8371-4185
  34. Johann S de Bono

    Prostate Cancer Target Therapy Group, Institute of Cancer Research, Sutton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  35. Andrew CB Cato

    Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany
    For correspondence
    andrew.cato@kit.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0001-8508-3834
  36. Myles Brown

    Department of Medical Oncology, Dana-Farber Cancer Instittue, Boston, United States
    For correspondence
    myles_brown@dfci.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-8213-1658

Funding

Prostate Cancer Foundation

  • Laura Cato
  • Adam Sharp
  • Johann S de Bono
  • Andrew CB Cato
  • Myles Brown

Deutsche Krebshilfe

  • Andrew CB Cato

Barr Foundation

  • Laura Cato

Prostate Cancer UK

  • Adam Sharp

Medical Research Council

  • Adam Sharp

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Chi Van Dang, Reviewing Editor, University of Pennsylvania, United States

Publication history

  1. Received: March 23, 2017
  2. Accepted: August 7, 2017
  3. Accepted Manuscript published: August 10, 2017 (version 1)

Copyright

© 2017, Cato et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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