Pharmacologic Inhibition of Lipogenesis Suppresses AR and Its Splice Variants to Inhibit Progression of Castration-Resistant Prostate Cancer
Abstract
A hallmark of prostate cancer progression is dysregulation of lipid metabolism via over expression of fatty acid synthase (FASN), a key enzyme in the de-novo fatty acids 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). We used a novel 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. These findings provide a rationale for the use of FASN inhibitors in CRPCs, including those overexpressing AR-V7.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2022
- Accession Number
- AD1191323
Entities
People
- Caroline F. Ribeiro
- Massimo Loda
- Scott M Dehm
- Stephen R Plymate
Organizations
- Cornell University
- University of Minnesota
- University of Washington