Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 2, Pages 631-640Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1808834116
Keywords
metastatic prostate cancer; fatty acid synthase; androgen signaling; AR-V7; metabolomics
Categories
Funding
- Department of Defense (DoD) IMPACT Grant [PC160357]
- DoD [W81XWH-14-2-0183, W81XWH1410405]
- NIH [R01-CA131945, P50 CA90381]
- Prostate Cancer Foundation (PCF)
- DoD Idea Development Award for New Investigators [PC150263]
- Claudia Adams Barr Award in Innovative Cancer Research from the Dana-Farber Cancer Institute
- Pacific Northwest Prostate Cancer Specialized Programs of Research Excellence (SPORE) [P50CA97186]
- Institute for Prostate Cancer Research
- Australian Research Council [FT130101004]
- Movember Foundation/PCF of Australia
- U.S. Department of Defense (DOD) [W81XWH1410405] Funding Source: U.S. Department of Defense (DOD)
- CDMRP [PC150263, 917681, PC160357, 893607] Funding Source: Federal RePORTER
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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.
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