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

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 journal › Article › peer-review

39 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 language	English (US)
Pages (from-to)	2355-2370.e6
Journal	Cell reports
Volume	29
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2019.10.068
State	Published - Nov 19 2019
Externally published	Yes

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)

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1016/j.celrep.2019.10.068

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Hwang, J. H., Seo, J. H., Beshiri, M. L., Wankowicz, S., Liu, D., Cheung, A., Li, J., Qiu, X., Hong, A. L., Botta, G., Golumb, L., Richter, C., So, J., Sandoval, G. J., Giacomelli, A. O., Ly, S. H., Han, C., Dai, C., Pakula, H., ... Hahn, W. C. (2019). CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer. Cell reports, 29(8), 2355-2370.e6. https://doi.org/10.1016/j.celrep.2019.10.068

Hwang, JH, Seo, JH, Beshiri, ML, Wankowicz, S, Liu, D, Cheung, A, Li, J, Qiu, X, Hong, AL, Botta, G, Golumb, L, Richter, C, So, J, Sandoval, GJ, Giacomelli, AO, Ly, SH, Han, C, Dai, C, Pakula, H, Sheahan, A, Piccioni, F, Gjoerup, O, Loda, M, Sowalsky, AG, Ellis, L, Long, H, Root, DE, Kelly, K, Van Allen, EM, Freedman, ML, Choudhury, AD & Hahn, WC 2019, 'CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer', Cell reports, vol. 29, no. 8, pp. 2355-2370.e6. https://doi.org/10.1016/j.celrep.2019.10.068

@article{7200569ed2b44e84b6c0819cb26ee2cf,

title = "CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer",

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",

author = "Hwang, {Justin H.} and Seo, {Ji Heui} and Beshiri, {Michael L.} and Stephanie Wankowicz and David Liu and Alexander Cheung and Ji Li and Xintao Qiu and Hong, {Andrew L.} and Ginevra Botta and Lior Golumb and Camden Richter and Jonathan So and Sandoval, {Gabriel J.} and Giacomelli, {Andrew O.} and Ly, {Seav Huong} and Celine Han and Chao Dai and Hubert Pakula and Anjali Sheahan and Federica Piccioni and Ole Gjoerup and Massimo Loda and Sowalsky, {Adam G.} and Leigh Ellis and Henry Long and Root, {David E.} and Kathleen Kelly and {Van Allen}, {Eliezer M.} and Freedman, {Matthew L.} and Choudhury, {Atish D.} and Hahn, {William C.}",

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: {\textcopyright} 2019 The Author(s)",

year = "2019",

month = nov,

day = "19",

doi = "10.1016/j.celrep.2019.10.068",

language = "English (US)",

volume = "29",

pages = "2355--2370.e6",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "8",

}

TY - JOUR

T1 - CREB5 Promotes Resistance to Androgen-Receptor Antagonists and Androgen Deprivation in Prostate Cancer

AU - Hwang, Justin H.

AU - Seo, Ji Heui

AU - Beshiri, Michael L.

AU - Wankowicz, Stephanie

AU - Liu, David

AU - Cheung, Alexander

AU - Li, Ji

AU - Qiu, Xintao

AU - Hong, Andrew L.

AU - Botta, Ginevra

AU - Golumb, Lior

AU - Richter, Camden

AU - So, Jonathan

AU - Sandoval, Gabriel J.

AU - Giacomelli, Andrew O.

AU - Ly, Seav Huong

AU - Han, Celine

AU - Dai, Chao

AU - Pakula, Hubert

AU - Sheahan, Anjali

AU - Piccioni, Federica

AU - Gjoerup, Ole

AU - Loda, Massimo

AU - Sowalsky, Adam G.

AU - Ellis, Leigh

AU - Long, Henry

AU - Root, David E.

AU - Kelly, Kathleen

AU - Van Allen, Eliezer M.

AU - Freedman, Matthew L.

AU - Choudhury, Atish D.

AU - Hahn, William C.

N1 - 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)

PY - 2019/11/19

Y1 - 2019/11/19

N2 - 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.

AB - 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.

KW - CREB5

KW - ORF screen

KW - androgen deprivation therapy

KW - androgen receptor

KW - metastatic castration-resistant prostate cancer

KW - therapy resistance

UR - http://www.scopus.com/inward/record.url?scp=85075126229&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075126229&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2019.10.068

DO - 10.1016/j.celrep.2019.10.068

M3 - Article

C2 - 31747605

AN - SCOPUS:85075126229

SN - 2211-1247

VL - 29

SP - 2355-2370.e6

JO - Cell reports

JF - Cell reports

IS - 8

ER -

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

Abstract

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Keywords

UN SDGs

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