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 language||English (US)|
|Number of pages||10|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Jan 8 2019|
Bibliographical noteFunding 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.
- Androgen signaling
- Fatty acid synthase
- Metastatic prostate cancer