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 SheahanFederica 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

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2355-2370.e6
JournalCell reports
Volume29
Issue number8
DOIs
StatePublished - Nov 19 2019
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the PCF/SU2C Prostate Cancer Dream Team (to E.M.V.A.), a PCF ? V Foundation Challenge Award (to E.M.V.A.), a PCF Young Investigator Award (to E.M.V.A. A.D.C. and A.G.S.), NIH K08 CA188615 (to E.M.V.A.), American Cancer Society ? AstraZeneca postdoctoral fellowship PF-16-142-01-TBE (to J.H.), a Susan G. Komen postdoctoral fellowship and a Terri Brodeur postdoctoral fellowship (to J.L.), DoD Prostate Cancer Research Program postdoctoral training award W81XWH-15-1-0659 (to G.J.S.), DoD PCRP Physician Research Training Award W81XWH-12-1-0062 (to A.D.C.), NCI U01 CA176058 (to W.C.H.), and the H.L. Snyder Foundation (to W.C.H. and M.L.F.). We thank Catherine Sypher and Zach Herbert for assistance. Conceptualization, J.H.H. L.G. E.M.V.A. M.L.F. A.D.C. W.C.H.; Methodologies, J.H.H. J.-H.S. M.L.B. D.L. A.C. X.Q. A.L.H. G.B. L.G. A.O.G. S.H.L. C.H. C.D. H.P. A.S. F.P. A.G.S. L.E. D.E.R. K.K. E.M.V.A. M.L.F. A.D.C.; Software, J.H.H. D.L. A.C. X.Q. C.H.; Validation, J.H.H. J.-H.S. M.L.B. J.L. X.Q. G.B. L.G. S.H.L. C.H. C.D. H.P. A.S.; Formal analysis, J.H.H. J.-H.S. M.L.B. D.L. A.C. J.L. X.Q. G.B. L.G. S.H.L. C.H. F.P. A.G.S.; Investigation, J.H.H. M.L.B. D.L. J.L. G.B. L.G. C.H. E.M.V.A.; Resources, J.H.H. H.L. D.E.R. K.K. E.M.V.A. M.L.F.; Data Curation, J.H.H. J.-H.S. M.L.B. D.L. A.C. X.Q. S.H.L. C.H. F.P.; Writing, J.H.H. J.L. A.L.H. D.E.R. E.M.V.A. A.D.C. W.C.H.; Visualization, J.H.H. S.H.L. W.C.H.; Supervision, J.H.H. A.L.H. A.O.G. O.G. M.L. L.E. H.L. K.K. E.M.V.A. M.L.F. W.C.H.; Project Administration, J.H.H. A.O.G. O.G. E.M.V.A. A.D.C. W.C.H.; Funding Acquisition, J.H.H. J.L. A.G.S. L.E. E.M.V.A. M.L.F. A.D.C. W.C.H. E.M.V.A. is a consultant of Tango Therapeutics, Invitae, Genome Medical, and Novartis. W.C.H. is a consultant for Thermo Fisher, AjuIB, MPM Capital, Frontier Medicines, and Parexel. W.C.H. is a founder and serves on the scientific advisory board of KSQ Therapeutics.

Funding Information:
This work was supported by the PCF/SU2C Prostate Cancer Dream Team (to E.M.V.A.), a PCF – V Foundation Challenge Award (to E.M.V.A.), a PCF Young Investigator Award (to E.M.V.A., A.D.C., and A.G.S.), NIH K08 CA188615 (to E.M.V.A.), American Cancer Society – AstraZeneca postdoctoral fellowship PF-16-142-01-TBE (to J.H.), a Susan G. Komen postdoctoral fellowship and a Terri Brodeur postdoctoral fellowship (to J.L.), DoD Prostate Cancer Research Program postdoctoral training award W81XWH-15-1-0659 (to G.J.S.), DoD PCRP Physician Research Training Award W81XWH-12-1-0062 (to A.D.C.), NCI U01 CA176058 (to W.C.H.), and the H.L. Snyder Foundation (to W.C.H. and M.L.F.). We thank Catherine Sypher and Zach Herbert for assistance.

Publisher Copyright:
© 2019 The Author(s)

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

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

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