Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/118042
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Zadra, G. | - |
dc.contributor.author | Ribeiro, C.F. | - |
dc.contributor.author | Chetta, P. | - |
dc.contributor.author | Ho, Y. | - |
dc.contributor.author | Cacciatore, S. | - |
dc.contributor.author | Gao, X. | - |
dc.contributor.author | Syamala, S. | - |
dc.contributor.author | Bango, C. | - |
dc.contributor.author | Photopoulos, C. | - |
dc.contributor.author | Huang, Y. | - |
dc.contributor.author | Tyekucheva, S. | - |
dc.contributor.author | Bastos, D.C. | - |
dc.contributor.author | Tchaicha, J. | - |
dc.contributor.author | Lawney, B. | - |
dc.contributor.author | Uo, T. | - |
dc.contributor.author | D'Anello, L. | - |
dc.contributor.author | Csibi, A. | - |
dc.contributor.author | Kalekar, R. | - |
dc.contributor.author | Larimer, B. | - |
dc.contributor.author | Ellis, L. | - |
dc.contributor.author | et al. | - |
dc.date.issued | 2019 | - |
dc.identifier.citation | Proceedings of the National Academy of Sciences of USA, 2019; 116(2):631-640 | - |
dc.identifier.issn | 0027-8424 | - |
dc.identifier.issn | 1091-6490 | - |
dc.identifier.uri | http://hdl.handle.net/2440/118042 | - |
dc.description.abstract | A hallmark of prostate cancer progression is dysregulation of lipid metabolism via overexpression of fatty acid synthase (FASN), a key enzyme in de novo fatty acid synthesis. Metastatic castration-resistant prostate cancer (mCRPC) develops resistance to inhibitors of androgen receptor (AR) signaling through a variety of mechanisms, including the emergence of the constitutively active AR variant V7 (AR-V7). Here, we developed an FASN inhibitor (IPI-9119) and demonstrated that selective FASN inhibition antagonizes CRPC growth through metabolic reprogramming and results in reduced protein expression and transcriptional activity of both full-length AR (AR-FL) and AR-V7. Activation of the reticulum endoplasmic stress response resulting in reduced protein synthesis was involved in IPI-9119-mediated inhibition of the AR pathway. In vivo, IPI-9119 reduced growth of AR-V7-driven CRPC xenografts and human mCRPC-derived organoids and enhanced the efficacy of enzalutamide in CRPC cells. In human mCRPC, both FASN and AR-FL were detected in 87% of metastases. AR-V7 was found in 39% of bone metastases and consistently coexpressed with FASN. In patients treated with enzalutamide and/or abiraterone FASN/AR-V7 double-positive metastases were found in 77% of cases. These findings provide a compelling rationale for the use of FASN inhibitors in mCRPCs, including those overexpressing AR-V7. | - |
dc.description.statementofresponsibility | Giorgia Zadra, Caroline F. Ribeiro, Paolo Chetta, Yeung Ho, Stefano Cacciatore ... Lisa M. Butler ... et al. | - |
dc.language.iso | en | - |
dc.publisher | National Academy of Sciences | - |
dc.rights | © 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). | - |
dc.source.uri | http://dx.doi.org/10.1073/pnas.1808834116 | - |
dc.subject | AR-V7 | - |
dc.subject | androgen signaling | - |
dc.subject | fatty acid synthase | - |
dc.subject | metabolomics | - |
dc.subject | metastatic prostate cancer | - |
dc.title | Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1073/pnas.1808834116 | - |
dc.relation.grant | http://purl.org/au-research/grants/arc/FT130101004 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Butler, L.M. [0000-0003-2698-3220] | - |
Appears in Collections: | Aurora harvest 3 Medicine publications |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
hdl_118042.pdf | Published version | 2.35 MB | Adobe PDF | View/Open |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.