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

doi:10.1016/j.celrep.2019.10.068

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

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

Authors

Justin H Hwang¹, Ji-Heui Seo², Michael L Beshiri³, Stephanie Wankowicz⁴, David Liu⁴, Alexander Cheung⁴, Ji Li¹, Xintao Qiu², Andrew L Hong¹, Ginevra Botta⁵, Lior Golumb¹, Camden Richter², Jonathan So¹, Gabriel J Sandoval¹, Andrew O Giacomelli¹, Seav Huong Ly¹, Celine Han¹, Chao Dai¹, Hubert Pakula², Anjali Sheahan¹, Federica Piccioni⁵, Ole Gjoerup², Massimo Loda¹, Adam G Sowalsky³, Leigh Ellis⁶, Henry Long², David E Root⁵, Kathleen Kelly³, Eliezer M Van Allen⁴, Matthew L Freedman¹, Atish D Choudhury¹, William C Hahn⁷

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Androgen Receptor Antagonists / therapeutic use*
Antineoplastic Agents / therapeutic use
Benzamides
Cyclic AMP Response Element-Binding Protein A / genetics
Cyclic AMP Response Element-Binding Protein A / metabolism*
Drug Resistance, Neoplasm / genetics
Humans
Male
Nitriles
Open Reading Frames / genetics
Phenylthiohydantoin / analogs & derivatives
Promoter Regions, Genetic / genetics
Prostatic Neoplasms, Castration-Resistant / drug therapy
Prostatic Neoplasms, Castration-Resistant / genetics
Receptors, Androgen / genetics
Receptors, Androgen / metabolism

Substances

Androgen Receptor Antagonists
Antineoplastic Agents
Benzamides
CREB5 protein, human
Cyclic AMP Response Element-Binding Protein A
Nitriles
Receptors, Androgen
Phenylthiohydantoin
enzalutamide

Abstract

Publication types

MeSH terms

Substances

Grants and funding