Targeting the BAG-1 family of co-chaperones in lethal prostate cancer
Author:
Neeb Antje, Figueiredo Ines, Bogdan Denisa, Cato Laura, Stober Jutta, Jimenez-Vacas Juan M., Gourain Victor, Lee Irene I., Seeger Rebecca, Muhle-Goll Claudia, Gurel Bora, Welti Jonathan, Rodrigues Daniel Nava, Rekowski Jan, Qiu Xintao, Jiang Yija, Di Micco Patrizio, Mateos Borja, Bielskutė Stasė, Riisnaes Ruth, Ferreira Ana, Miranda Susana, Crespo Mateus, Buroni Lorenzo, Ning Jian, Bräse Stefan, Jung Nicole, Gräßle Simone, Metzger Daniel, Swain Amanda, Salvatella Xavier, Plymate Stephen R., Al-Lazikani Bissan, Long HenryORCID, Yuan Wei, Brown Myles, Cato Andrew C. B., de Bono Johann S., Sharp Adam
Abstract
AbstractTherapies that abrogate persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain (NTD) of the AR drives transcriptional activity in CRPC but is intrinsically disordered and remains a challenging therapeutic target. Therefore, inhibiting critical co-chaperones, such as BAG-1L, is an attractive alternative strategy. We performed druggability analyses demonstrating the BAG domain to be a challenging drug target. Thio-2, a tool compound, has been reported to bind the BAG domain of BAG-1L and inhibit BAG-1L-mediated AR transactivation. However, despite these data, the mechanism of action of Thio-2 is poorly understood and the BAG domain which is present in all BAG-1 isoforms has not been validated as a therapeutic target. Herein, we demonstrate growth inhibiting activity of Thio-2 in CRPC cell lines and patient derived models with decreased AR genomic binding and AR signaling independent of BAG-1 isoform function. Furthermore, genomic abrogation of BAG-1 isoforms did not recapitulate the described Thio-2 phenotype, and NMR studies suggest that Thio-2 may bind the AR NTD, uncovering a potential alternative mechanism of action, although in the context of low compound solubility. Furthermore, BAG-1 isoform knockout mice are viable and fertile, in contrast to previous studies, and when crossed with prostate cancer mouse models, BAG-1 deletion does not significantly impact prostate cancer development and growth. Overall, these data demonstrate that Thio-2 inhibits AR signaling and growth in CRPC independent of BAG-1 isoforms, and unlike previous studies of the activated AR, therapeutic targeting of the BAG domain requires further validation before being considered a therapeutic strategy for the treatment of CRPC.
Publisher
Cold Spring Harbor Laboratory
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