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

Justin H. Hwang(Broad Institute), Ji-Heui Seo(Dana-Farber Cancer Institute), Michael L. Beshiri(Center for Cancer Research), Stephanie A. Wankowicz(Dana-Farber Cancer Institute), David Liu(Dana-Farber Cancer Institute), Alexander T. M. Cheung(Broad Institute), Ji Li(Dana-Farber Cancer Institute), Xintao Qiu(Dana-Farber Cancer Institute), Andrew L. Hong(Broad Institute), Ginevra Botta(Broad Institute), Lior Golumb(Dana-Farber Cancer Institute), Camden Richter(Dana-Farber Cancer Institute), Jonathan So(Dana-Farber Cancer Institute), Gabriel J. Sandoval(Dana-Farber Cancer Institute), Andrew O. Giacomelli(Dana-Farber Cancer Institute), Seav Huong Ly(Broad Institute), G. Celine Han(Dana-Farber Cancer Institute), Chao Dai(Dana-Farber Cancer Institute), Hubert Pakula(Dana-Farber Cancer Institute), Anjali V. Sheahan(Broad Institute), Federica Piccioni(Broad Institute), Ole Gjoerup(Dana-Farber Cancer Institute), Massimo Loda(Broad Institute), Adam G. Sowalsky(Center for Cancer Research), Leigh Ellis(Broad Institute), Henry W. Long(Dana-Farber Cancer Institute), David E. Root(Broad Institute), Kathleen Kelly(National Cancer Institute), Eliezer M. Van Allen(Broad Institute), Matthew L. Freedman(Dana-Farber Cancer Institute), Atish D. Choudhury(Dana-Farber Cancer Institute), William C. Hahn(Broad Institute)
Cell Reports
November 1, 2019
10.1016/j.celrep.2019.10.068
Cited by 78Open Access
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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.

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