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

Giorgia Zadra, Caroline F Ribeiro, Paolo Chetta, Yeung Ho, Stefano Cacciatore, Xueliang Gao, Sudeepa Syamala, Clyde Bango, Cornelia Photopoulos, Ying Huang, Svitlana Tyekucheva, Debora C Bastos, Jeremy Tchaicha, Brian Lawney, Takuma Uo, Laura D'Anello, Alfredo Csibi, Radha Kalekar, Benjamin Larimer, Leigh Ellis & 12 others Lisa M Butler, Colm Morrissey, Karen McGovern, Vito J Palombella, Jeffery L Kutok, Umar Mahmood, Silvano Bosari, Julian Adams, Stephane Peluso, Scott M Dehm, Stephen R Plymate, Massimo Loda

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

LanguageEnglish
Pages631-640
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number2
DOIs
Publication statusPublished - 8 Jan 2019

Keywords

  • Metastatic Prostate Cancer
  • Fatty Acid Synthases
  • androgen signaling
  • AR-V7
  • metabolomics

Cite this

Zadra, Giorgia ; Ribeiro, Caroline F ; Chetta, Paolo ; Ho, Yeung ; Cacciatore, Stefano ; Gao, Xueliang ; Syamala, Sudeepa ; Bango, Clyde ; Photopoulos, Cornelia ; Huang, Ying ; Tyekucheva, Svitlana ; Bastos, Debora C ; Tchaicha, Jeremy ; Lawney, Brian ; Uo, Takuma ; D'Anello, Laura ; Csibi, Alfredo ; Kalekar, Radha ; Larimer, Benjamin ; Ellis, Leigh ; Butler, Lisa M ; Morrissey, Colm ; McGovern, Karen ; Palombella, Vito J ; Kutok, Jeffery L ; Mahmood, Umar ; Bosari, Silvano ; Adams, Julian ; Peluso, Stephane ; Dehm, Scott M ; Plymate, Stephen R ; Loda, Massimo. / Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 2. pp. 631-640.
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title = "Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer",
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 = "Metastatic Prostate Cancer, Fatty Acid Synthases, androgen signaling, AR-V7, metabolomics",
author = "Giorgia Zadra and Ribeiro, {Caroline F} and Paolo Chetta and Yeung Ho and Stefano Cacciatore and Xueliang Gao and Sudeepa Syamala and Clyde Bango and Cornelia Photopoulos and Ying Huang and Svitlana Tyekucheva and Bastos, {Debora C} and Jeremy Tchaicha and Brian Lawney and Takuma Uo and Laura D'Anello and Alfredo Csibi and Radha Kalekar and Benjamin Larimer and Leigh Ellis and Butler, {Lisa M} and Colm Morrissey and Karen McGovern and Palombella, {Vito J} and Kutok, {Jeffery L} and Umar Mahmood and Silvano Bosari and Julian Adams and Stephane Peluso and Dehm, {Scott M} and Plymate, {Stephen R} and Massimo Loda",
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Zadra, G, Ribeiro, CF, Chetta, P, Ho, Y, Cacciatore, S, Gao, X, Syamala, S, Bango, C, Photopoulos, C, Huang, Y, Tyekucheva, S, Bastos, DC, Tchaicha, J, Lawney, B, Uo, T, D'Anello, L, Csibi, A, Kalekar, R, Larimer, B, Ellis, L, Butler, LM, Morrissey, C, McGovern, K, Palombella, VJ, Kutok, JL, Mahmood, U, Bosari, S, Adams, J, Peluso, S, Dehm, SM, Plymate, SR & Loda, M 2019, 'Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 2, pp. 631-640. https://doi.org/10.1073/pnas.1808834116

Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer. / Zadra, Giorgia; Ribeiro, Caroline F; Chetta, Paolo; Ho, Yeung; Cacciatore, Stefano; Gao, Xueliang; Syamala, Sudeepa; Bango, Clyde; Photopoulos, Cornelia; Huang, Ying; Tyekucheva, Svitlana; Bastos, Debora C; Tchaicha, Jeremy; Lawney, Brian; Uo, Takuma; D'Anello, Laura; Csibi, Alfredo; Kalekar, Radha; Larimer, Benjamin; Ellis, Leigh; Butler, Lisa M; Morrissey, Colm; McGovern, Karen; Palombella, Vito J; Kutok, Jeffery L; Mahmood, Umar; Bosari, Silvano; Adams, Julian; Peluso, Stephane; Dehm, Scott M; Plymate, Stephen R; Loda, Massimo.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 2, 08.01.2019, p. 631-640.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer

AU - Zadra, Giorgia

AU - Ribeiro, Caroline F

AU - Chetta, Paolo

AU - Ho, Yeung

AU - Cacciatore, Stefano

AU - Gao, Xueliang

AU - Syamala, Sudeepa

AU - Bango, Clyde

AU - Photopoulos, Cornelia

AU - Huang, Ying

AU - Tyekucheva, Svitlana

AU - Bastos, Debora C

AU - Tchaicha, Jeremy

AU - Lawney, Brian

AU - Uo, Takuma

AU - D'Anello, Laura

AU - Csibi, Alfredo

AU - Kalekar, Radha

AU - Larimer, Benjamin

AU - Ellis, Leigh

AU - Butler, Lisa M

AU - Morrissey, Colm

AU - McGovern, Karen

AU - Palombella, Vito J

AU - Kutok, Jeffery L

AU - Mahmood, Umar

AU - Bosari, Silvano

AU - Adams, Julian

AU - Peluso, Stephane

AU - Dehm, Scott M

AU - Plymate, Stephen R

AU - Loda, Massimo

N1 - Copyright © 2019 the Author(s). Published by PNAS.

PY - 2019/1/8

Y1 - 2019/1/8

N2 - 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.

AB - 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.

KW - Metastatic Prostate Cancer

KW - Fatty Acid Synthases

KW - androgen signaling

KW - AR-V7

KW - metabolomics

U2 - 10.1073/pnas.1808834116

DO - 10.1073/pnas.1808834116

M3 - Article

VL - 116

SP - 631

EP - 640

JO - Proceedings of the National Academy of Sciences of the United States of America

T2 - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 2

ER -