Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer Academic Article uri icon


MeSH Major

  • Breast Neoplasms
  • Genes, erbB-2
  • Immunomagnetic Separation
  • Neoplastic Cells, Circulating


  • 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.


publication date

  • January 8, 2019



  • Academic Article



  • eng

PubMed Central ID

  • PMC6329966

Digital Object Identifier (DOI)

  • 10.1073/pnas.1808834116

PubMed ID

  • 30578319

Additional Document Info

start page

  • 631

end page

  • 640


  • 116


  • 2