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

• DOI: 10.1016/j.celrep.2019.10.068
• Publication Date: 2019-11-19T15:45:54Z
• Authors: 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
• Keywords: Enzalutamide

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 in an open reading frame (ORF) expression screen and tumor xenografts. overexpression is essential enzalutamide-resistant patient-derived organoid. In AR-expressing cancer cells, interactions enhance AR activity at a subset promoters enhancers upon treatment, MYC genes involved cell cycle. mCRPC, we found recurrent amplification CREB5. Our observations identify as one mechanism drives to antagonists cancers.