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

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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 (US)
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
StatePublished - Jan 8 2019

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. This work was supported by Department of Defense (DoD) IMPACT Grant PC160357 (to M.L., S.M.D., and S.R.P.), DoD synergistic Grant W81XWH1410405 (to M.L. and U.M.), NIH Grants R01-CA131945 and P50 CA90381, and the Prostate Cancer Foundation (PCF) (M.L.). G.Z. is a recipient of the DoD Idea Development Award for New Investigators (PC150263) and a Claudia Adams Barr Award in Innovative Cancer Research from the Dana-Farber Cancer Institute. The rapid autopsy material is the result of work supported by resources by the DoD (Award W81XWH-14-2-0183), the Pacific Northwest Prostate Cancer Specialized Programs of Research Excellence (SPORE) (Grant P50CA97186), and the Institute for Prostate Cancer Research. L. M.B. is supported by a Future Fellowship from the Australian Research Council (Fellowship FT130101004) and grant support from the Movember Foundation/ PCF of Australia.

Keywords

  • AR-V7
  • Androgen signaling
  • Fatty acid synthase
  • Metabolomics
  • Metastatic prostate cancer

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