Details

Autor(en) / Beteiligte

• Hwang, Justin H.
• Seo, Ji-Heui
• Beshiri, Michael L.
• Wankowicz, Stephanie
• Liu, David
• Cheung, Alexander
• Li, Ji
• Qiu, Xintao
• Hong, Andrew L.
• Botta, Ginevra
• Golumb, Lior
• Richter, Camden
• So, Jonathan
• Sandoval, Gabriel J.
• Giacomelli, Andrew O.
• Ly, Seav Huong
• Han, Celine
• Dai, Chao
• Pakula, Hubert
• Sheahan, Anjali
• Piccioni, Federica
• Gjoerup, Ole
• Loda, Massimo
• Sowalsky, Adam G.
• Ellis, Leigh
• Long, Henry
• Root, David E.
• Kelly, Kathleen
• Van Allen, Eliezer M.
• Freedman, Matthew L.
• Choudhury, Atish D.
• Hahn, William C.

Titel

CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer

Ist Teil von

• Cell reports (Cambridge), 2019-11, Vol.29 (8), p.2355-2370.e6

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Androgen-receptor (AR) inhibitors, including enzalutamide, are used for treatment of all metastatic castration-resistant prostate cancers (mCRPCs). However, some patients develop resistance or never respond. We find that the transcription factor CREB5 confers enzalutamide resistance in an open reading frame (ORF) expression screen and in tumor xenografts. CREB5 overexpression is essential for an enzalutamide-resistant patient-derived organoid. In AR-expressing prostate cancer cells, CREB5 interactions enhance AR activity at a subset of promoters and enhancers upon enzalutamide treatment, including MYC and genes involved in the cell cycle. In mCRPC, we found recurrent amplification and overexpression of CREB5. Our observations identify CREB5 as one mechanism that drives resistance to AR antagonists in prostate cancers. [Display omitted] •CREB5 promotes resistance to AR inhibitors and androgen therapies in prostate cancer•CREB5 selectively enhances interaction of AR with target genes critical for survival•CREB5 is amplified or overexpressed in therapy-resistant metastatic prostate cancers•Targeting CREB5 is effective in patient-derived models that are therapy resistant Advanced prostate cancers develop resistance to androgen receptor (AR)-targeting therapies. Hwang et al. show that resistant prostate cancers overexpress or amplify CREB5, mediating resistance to AR inhibition. CREB5 suppression reduces the viability of therapy-resistant patient-derived models, suggesting that CREB5 is a target in prostate cancer patients with limited treatment options.