Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer

Giorgia Zadra, Caroline F Ribeiro, Paolo Chetta, Yeung Ho, Stefano Cacciatore, Xueliang Gao, Sudeepa Syamala, Clyde Bango, Cornelia Photopoulos, Ying Huang, Svitlana Tyekucheva, Debora C Bastos, Jeremy Tchaicha, Brian Lawney, Takuma Uo, Laura D'Anello, Alfredo Csibi, Radha Kalekar, Benjamin Larimer, Leigh EllisLisa M Butler, Colm Morrissey, Karen McGovern, Vito J Palombella, Jeffery L Kutok, Umar Mahmood, Silvano Bosari, Julian Adams, Stephane Peluso, Scott M Dehm, Stephen R Plymate, Massimo Loda

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31 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)631-640
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number2
DOIs
Publication statusPublished - 8 Jan 2019

Keywords

  • Metastatic Prostate Cancer
  • Fatty Acid Synthases
  • androgen signaling
  • AR-V7
  • metabolomics

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