2. Academic Validation
  3. Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer

Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer

  • Proc Natl Acad Sci U S A. 2019 Jan 8;116(2):631-640. doi: 10.1073/pnas.1808834116.
Giorgia Zadra 1 2,  Caroline F Ribeiro 3,  Paolo Chetta 3 4,  Yeung Ho 5,  Stefano Cacciatore 6 7,  Xueliang Gao 8,  Sudeepa Syamala 3,  Clyde Bango 3,  Cornelia Photopoulos 3,  Ying Huang 3,  Svitlana Tyekucheva 9 10,  Debora C Bastos 11,  Jeremy Tchaicha 12,  Brian Lawney 13,  Takuma Uo 14,  Laura D'Anello 3,  Alfredo Csibi 12,  Radha Kalekar 3,  Benjamin Larimer 15,  Leigh Ellis 3 2 16,  Lisa M Butler 17 18 19,  Colm Morrissey 14,  Karen McGovern 12,  Vito J Palombella 12,  Jeffery L Kutok 12,  Umar Mahmood 15,  Silvano Bosari 20 21,  Julian Adams 12,  Stephane Peluso 12,  Scott M Dehm 5 22 23,  Stephen R Plymate 14,  Massimo Loda 1 2 16
Affiliations

Affiliations

  • 1 Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215; [email protected] [email protected].
  • 2 Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115.
  • 3 Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215.
  • 4 Residency Program in Pathology, University of Milan, 20122 Milan, Italy.
  • 5 Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455.
  • 6 Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom.
  • 7 Cancer Genomics Group, International Centre for Genetic Engineering and Biotechnology, Observatory 7925, Cape Town, South Africa.
  • 8 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
  • 9 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
  • 10 Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115.
  • 11 Department of Oral Diagnosis, University of Campinas, 13414-093 Piracicaba, Brazil.
  • 12 Infinity Pharmaceuticals, Inc., Cambridge, MA 02139.
  • 13 Center for Cancer Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
  • 14 Department of Urology, University of Washington, Seattle, WA, 98195.
  • 15 Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA 02114.
  • 16 Broad Institute, Cambridge, MA 02142.
  • 17 Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia.
  • 18 Freemasons Foundation Centre for Men's Health, University of Adelaide, Adelaide, SA 5005, Australia.
  • 19 South Australian Health and Medical Research Institute, Adelaide, SA 5001, Australia.
  • 20 Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy.
  • 21 Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Foundation Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy.
  • 22 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455.
  • 23 Department of Urology, University of Minnesota, Minneapolis, MN 55455.
PMID: 30578319 DOI: 10.1073/pnas.1808834116
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.

Keywords

AR-V7; androgen signaling; fatty acid synthase; metabolomics; metastatic prostate cancer.

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