Cell Reports (Nov 2019)
CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer
- Justin H. Hwang,
- Ji-Heui Seo,
- Michael L. Beshiri,
- Stephanie Wankowicz,
- David Liu,
- Alexander Cheung,
- Ji Li,
- Xintao Qiu,
- Andrew L. Hong,
- Ginevra Botta,
- Lior Golumb,
- Camden Richter,
- Jonathan So,
- Gabriel J. Sandoval,
- Andrew O. Giacomelli,
- Seav Huong Ly,
- Celine Han,
- Chao Dai,
- Hubert Pakula,
- Anjali Sheahan,
- Federica Piccioni,
- Ole Gjoerup,
- Massimo Loda,
- Adam G. Sowalsky,
- Leigh Ellis,
- Henry Long,
- David E. Root,
- Kathleen Kelly,
- Eliezer M. Van Allen,
- Matthew L. Freedman,
- Atish D. Choudhury,
- William C. Hahn
Affiliations
- Justin H. Hwang
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Ji-Heui Seo
- Dana-Farber Cancer Institute, Boston, MA, USA
- Michael L. Beshiri
- Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
- Stephanie Wankowicz
- 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
- David Liu
- 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
- Alexander Cheung
- 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
- Ji Li
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Xintao Qiu
- Dana-Farber Cancer Institute, Boston, MA, USA
- Andrew L. Hong
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Ginevra Botta
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Lior Golumb
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Camden Richter
- Dana-Farber Cancer Institute, Boston, MA, USA
- Jonathan So
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Gabriel J. Sandoval
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Andrew O. Giacomelli
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Seav Huong Ly
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Celine Han
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Chao Dai
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Hubert Pakula
- Dana-Farber Cancer Institute, Boston, MA, USA
- Anjali Sheahan
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Federica Piccioni
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Ole Gjoerup
- Dana-Farber Cancer Institute, Boston, MA, USA
- Massimo Loda
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Adam G. Sowalsky
- Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
- Leigh Ellis
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Brigham and Women’s Hospital, Boston, MA, USA
- Henry Long
- Dana-Farber Cancer Institute, Boston, MA, USA
- David E. Root
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Kathleen Kelly
- Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
- Eliezer M. Van Allen
- 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
- Matthew L. Freedman
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Atish D. Choudhury
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA
- William C. Hahn
- Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of Harvard and MIT, Cambridge, MA, USA; Brigham and Women’s Hospital, Boston, MA, USA; Corresponding author
- Journal volume & issue
-
Vol. 29,
no. 8
pp. 2355 – 2370.e6
Abstract
Summary: 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. : 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. Keywords: metastatic castration-resistant prostate cancer, androgen deprivation therapy, therapy resistance, CREB5, androgen receptor, ORF screen
