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
  • 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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