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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
Proceedings of the National Academy of Sciences, 01/2019, Letnik: 116, Številka: 2Journal Article
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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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