Abstract
Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 279-296.e9 |
| Journal | Cancer Cell |
| Volume | 38 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 10 2020 |
Keywords
- NRG1/neuregulin 1
- cancer-associated fibroblast
- drug resistance
- hormone therapy
- tumor microenvironment
ASJC Scopus subject areas
- Oncology
- Cell Biology
- Cancer Research
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Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer. / Zhang, Zeda; Karthaus, Wouter R.; Lee, Young Sun; Gao, Vianne R.; Wu, Chao; Russo, Joshua W.; Liu, Menghan; Mota, Jose Mauricio; Abida, Wassim; Linton, Eliot; Lee, Eugine; Barnes, Spencer D.; Chen, Hsuan An; Mao, Ninghui; Wongvipat, John; Choi, Danielle; Chen, Xiaoping; Zhao, Huiyong; Manova-Todorova, Katia; de Stanchina, Elisa; Taplin, Mary Ellen; Balk, Steven P.; Rathkopf, Dana E.; Gopalan, Anuradha; Carver, Brett S.; Mu, Ping; Jiang, Xuejun; Watson, Philip A.; Sawyers, Charles L.
In: Cancer Cell, Vol. 38, No. 2, 10.08.2020, p. 279-296.e9.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer
AU - Zhang, Zeda
AU - Karthaus, Wouter R.
AU - Lee, Young Sun
AU - Gao, Vianne R.
AU - Wu, Chao
AU - Russo, Joshua W.
AU - Liu, Menghan
AU - Mota, Jose Mauricio
AU - Abida, Wassim
AU - Linton, Eliot
AU - Lee, Eugine
AU - Barnes, Spencer D.
AU - Chen, Hsuan An
AU - Mao, Ninghui
AU - Wongvipat, John
AU - Choi, Danielle
AU - Chen, Xiaoping
AU - Zhao, Huiyong
AU - Manova-Todorova, Katia
AU - de Stanchina, Elisa
AU - Taplin, Mary Ellen
AU - Balk, Steven P.
AU - Rathkopf, Dana E.
AU - Gopalan, Anuradha
AU - Carver, Brett S.
AU - Mu, Ping
AU - Jiang, Xuejun
AU - Watson, Philip A.
AU - Sawyers, Charles L.
N1 - Funding Information: C.L.S. and J.W. are co-inventors of enzalutamide and apalutamide and may be entitled to royalties. C.L.S. serves on the Board of Directors of Novartis and is a co-founder of ORIC Pharmaceuticals. He is a science advisor to Agios, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, Petra, and PMV. W.A. reports consulting for Clovis Oncology, Janssen, MORE Health, and ORIC Pharmaceuticals, and received honoraria from CARET and travel accommodations from GlaxoSmith Kline, Clovis Oncology, and ORIC Pharmaceuticals. D.E.R. reports having consulting or advisory role (uncompensated) from Genentech/Roche, Janssen Oncology, and TRACON Pharma, and received research funding from: AstraZeneca (Inst); Celgene (Inst); Ferring (Inst); Genentech / Roche (Inst); Janssen Oncology (Inst); Medivation / Astellas / Pfizer (Inst); Millennium (Inst); Novartis (Inst); Taiho Pharmaceutical (Inst); Takeda (Inst); TRACON Pharma (Inst). W.R.K. is a coinventor on patent WO2012168930A2 filed by Koninklijke Nederlandse Akademie Van Wetenschappen that covers organoid technology. Funding Information: We thank cBioportal and the TCGA research network for providing us access to genomic and transcriptomic data. We thank Elizabeth Adams Whicher for critical input in revising the manuscript. We thank Rohit Bose, Phil Iaquinta, J. Joshua Smith, and all members of the Sawyers laboratory for comments, Memorial Sloan Kettering Cancer Center core facilities, Ning Fan, Mesruh Turkekul, Afsar Barlas, Dmitry Yarilin, Sho Fujisawa, and Sharon Huang from the MSKCC Molecular Cytology Core Facility and Juan Qiu and Qing Chang from the MSKCC Antitumor Assessment Core Facility. We thank Ann Bialik who performed NRG1 IHC staining in clinical specimens. We thank Sarat Chandalarpaty and Neal Rosen who provided us the AMG888 (U3-1287) antibody. We thank Han Yuan and Xiaoyi Li who provided expertise and suggestions for bioinformatics analysis, and Samir Zaidi who helped perform alignment and gene quantification for 22Pc-EP RNA-seq experiment. This work is partially supported by National Cancer Institute ( R01CA155169–04 and R01CA19387-01 to C.L.S., R01 CA166413 and R01 CA204232 to X.J., R00CA218885-04 to P.M., P30CA008748 and U54OD020355 to E.d.S.), Howard Hughes Medical Institute ( DT0712 to C.L.S.), NIH/NCI/ MSKCC Spore in Prostate Cancer ( P50 CA092629-14 to C.L.S.), NCI /MSKCC Support Grant/Core Grant ( P30CA008748-49 and P3CA008748-49-S2 to C.L.S.) and the Starr Cancer Consortium ( I9-A9- 071 to C.L.S.), Department of Defense ( PC170900 to P.M., W81XWH-18-1-0379 to S.P.B and J.W.R.), Cancer Prevention Research Institute (CPRIT RR170050 to P.M., RP150596 to S.B.), the Vallee Foundation , the Prostate Cancer Foundation ( 17YOUN12 to P.M., 17YOUN10 to W.R.K. and 18YOUNG24 to J.W.R.), Dutch Cancer Foundation (to W.R.K.), Welch Foundation ( I-2005-20190330 to P.M.), the WorldQuant Foundation , The Pershing Square Sohn Cancer Research Alliance , the NIH ( 1R01MH117406 ), UTSW Deborah and W.A. Tex Moncrief, Jr., Scholar (to P.M.), UTSW Harold C. Simmons Cancer Center Pilot Award, USA (to P.M.), The molecular cytology core at MSKCC ( P30 CA008748 ). Z.Z. is supported by the NCI Predoctoral to Postdoctoral Fellow F99/K00 Transition Award ( F99CA223063 ). Funding Information: We thank cBioportal and the TCGA research network for providing us access to genomic and transcriptomic data. We thank Elizabeth Adams Whicher for critical input in revising the manuscript. We thank Rohit Bose, Phil Iaquinta, J. Joshua Smith, and all members of the Sawyers laboratory for comments, Memorial Sloan Kettering Cancer Center core facilities, Ning Fan, Mesruh Turkekul, Afsar Barlas, Dmitry Yarilin, Sho Fujisawa, and Sharon Huang from the MSKCC Molecular Cytology Core Facility and Juan Qiu and Qing Chang from the MSKCC Antitumor Assessment Core Facility. We thank Ann Bialik who performed NRG1 IHC staining in clinical specimens. We thank Sarat Chandalarpaty and Neal Rosen who provided us the AMG888 (U3-1287) antibody. We thank Han Yuan and Xiaoyi Li who provided expertise and suggestions for bioinformatics analysis, and Samir Zaidi who helped perform alignment and gene quantification for 22Pc-EP RNA-seq experiment. This work is partially supported by National Cancer Institute (R01CA155169?04 and R01CA19387-01 to C.L.S. R01 CA166413 and R01 CA204232 to X.J. R00CA218885-04 to P.M. P30CA008748 and U54OD020355 to E.d.S.), Howard Hughes Medical Institute (DT0712 to C.L.S.), NIH/NCI/MSKCC Spore in Prostate Cancer (P50 CA092629-14 to C.L.S.), NCI/MSKCC Support Grant/Core Grant (P30CA008748-49 and P3CA008748-49-S2 to C.L.S.) and the Starr Cancer Consortium (I9-A9- 071 to C.L.S.), Department of Defense (PC170900 to P.M. W81XWH-18-1-0379 to S.P.B and J.W.R.), Cancer Prevention Research Institute (CPRIT RR170050 to P.M. RP150596 to S.B.), the Vallee Foundation, the Prostate Cancer Foundation (17YOUN12 to P.M. 17YOUN10 to W.R.K. and 18YOUNG24 to J.W.R.), Dutch Cancer Foundation (to W.R.K.), Welch Foundation (I-2005-20190330 to P.M.), the WorldQuant Foundation, The Pershing Square Sohn Cancer Research Alliance, the NIH (1R01MH117406), UTSW Deborah and W.A. Tex Moncrief, Jr. Scholar (to P.M.), UTSW Harold C. Simmons Cancer Center Pilot Award, USA (to P.M.), The molecular cytology core at MSKCC (P30 CA008748). Z.Z. is supported by the NCI Predoctoral to Postdoctoral Fellow F99/K00 Transition Award (F99CA223063). Z.Z. P.A.W. and C.L.S. conceived the project. Z.Z. B.S.C. P.M. W.R.K. P.A.W. and C.L.S. oversaw the project, performed experimental design, and data interpretation. Z.Z. P.A.W. and C.L.S. wrote the manuscript. Z.Z. J.W. D.C. C.W. E. Lee. X.C. and H.Z. performed the in vivo experiments. Z.Z. and X.J. performed the biochemical fractionation assays. Z.Z. P.A.W. Y.S.L. H.-A.C. and N.M. cloned plasmid reagents. Z.Z. H.A.-C. and Y.S.L. performed western blots, in vitro growth assay, and qRT-PCR analysis. V.R.G. and E. Linton. performed bioinformatics analysis in TCGA and SU2C patient data. M.L. performed bioinformatics analysis to 22Pc-EP RNA-seq data. A.G. performed immunohistochemistry analysis in patient tissues. B.S.C. A.G. and J.M.M. performed pathology analysis in patient tissues. D.E.R. W.A. P.M. and J.M.M. performed clinical analysis for patient tissues. S.P.B. M.-E.T. and J.W.R. provided primary neoadjuvant ADT clinical samples. K.M.-T. supervised immunohistochemistry and RNA in situ hybridization experiments. E.d.S. supervised in vivo experiments. C.L.S. and J.W. are co-inventors of enzalutamide and apalutamide and may be entitled to royalties. C.L.S. serves on the Board of Directors of Novartis and is a co-founder of ORIC Pharmaceuticals. He is a science advisor to Agios, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, Petra, and PMV. W.A. reports consulting for Clovis Oncology, Janssen, MORE Health, and ORIC Pharmaceuticals, and received honoraria from CARET and travel accommodations from GlaxoSmith Kline, Clovis Oncology, and ORIC Pharmaceuticals. D.E.R. reports having consulting or advisory role (uncompensated) from Genentech/Roche, Janssen Oncology, and TRACON Pharma, and received research funding from: AstraZeneca (Inst); Celgene (Inst); Ferring (Inst); Genentech/Roche (Inst); Janssen Oncology (Inst); Medivation/Astellas/Pfizer (Inst); Millennium (Inst); Novartis (Inst); Taiho Pharmaceutical (Inst); Takeda (Inst); TRACON Pharma (Inst). W.R.K. is a coinventor on patent WO2012168930A2 filed by Koninklijke Nederlandse Akademie Van Wetenschappen that covers organoid technology. Publisher Copyright: © 2020 The Authors
PY - 2020/8/10
Y1 - 2020/8/10
N2 - Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies.
AB - Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies.
KW - NRG1/neuregulin 1
KW - cancer-associated fibroblast
KW - drug resistance
KW - hormone therapy
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85088935584&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85088935584&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2020.06.005
DO - 10.1016/j.ccell.2020.06.005
M3 - Article
C2 - 32679108
AN - SCOPUS:85088935584
VL - 38
SP - 279-296.e9
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 2
ER -