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Type: Journal article
Title: Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer
Author: Zadra, G.
Ribeiro, C.F.
Chetta, P.
Ho, Y.
Cacciatore, S.
Gao, X.
Syamala, S.
Bango, C.
Photopoulos, C.
Huang, Y.
Tyekucheva, S.
Bastos, D.C.
Tchaicha, J.
Lawney, B.
Uo, T.
D'Anello, L.
Csibi, A.
Kalekar, R.
Larimer, B.
Ellis, L.
et al.
Citation: Proceedings of the National Academy of Sciences of USA, 2019; 116(2):631-640
Publisher: National Academy of Sciences
Issue Date: 2019
ISSN: 0027-8424
Statement of
Giorgia Zadra, Caroline F. Ribeiro, Paolo Chetta, Yeung Ho, Stefano Cacciatore ... Lisa M. Butler ... et al.
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.
Keywords: AR-V7
androgen signaling
fatty acid synthase
metastatic prostate cancer
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).
DOI: 10.1073/pnas.1808834116
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