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Cell Rep. 2019 Nov 19;29(8):2355-2370.e6. doi: 10.1016/j.celrep.2019.10.068.

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

Author information

1
Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
2
Dana-Farber Cancer Institute, Boston, MA, USA.
3
Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
4
Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA, USA.
5
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
6
Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Brigham and Women's Hospital, Boston, MA, USA.
7
Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Brigham and Women's Hospital, Boston, MA, USA. Electronic address: william_hahn@dfci.harvard.edu.

Abstract

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.

KEYWORDS:

CREB5; ORF screen; androgen deprivation therapy; androgen receptor; metastatic castration-resistant prostate cancer; therapy resistance

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