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

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ICR Authors

Sharp, Adam
 Nava Rodrigues, Daniel
 Rescigno, Pasquale
 Figueiredo, Ines
 Al-Lazikani, Bissan
 De Bono, Johann

Authors

Cato, L
Neeb, A
Sharp, A
Buzón, V
Ficarro, SB
Yang, L
Muhle-Goll, C
Kuznik, NC
Riisnaes, R
Nava Rodrigues, D
Armant, O
Gourain, V
Adelmant, G
Ntim, EA
Westerling, T
Dolling, D
Rescigno, P
Figueiredo, I
Fauser, F
Wu, J
Rottenberg, JT
Shatkina, L
Ester, C
Luy, B
Puchta, H
Troppmair, J
Jung, N
Bräse, S
Strähle, U
Marto, JA
Nienhaus, GU
Al-Lazikani, B
Salvatella, X
de Bono, JS
Cato, AC
Brown, M

Document Type

Journal Article

Date

2017-08-10

Date Accepted

2017-08-07

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.

Citation

eLife, 2017, 6

DOI

10.7554/elife.27159

URI

https://repository.icr.ac.uk/handle/internal/945

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

ELIFE SCIENCES PUBLICATIONS LTD

ISSN

2050-084X

eISSN

2050-084X

Collections

Cancer Therapeutics
Clinical Studies

Research Team

Computational Biology and Chemogenomics
Prostate Cancer Targeted Therapy Group
Translational Therapeutics

Notes