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Genome-scale genetic screening identifies PRMT1 as a critical vulnerability in castration-resistant prostate cancer

View ORCID ProfileStephen Tang, Nebiyou Y. Metaferia, Marina F. Nogueira, Maya K. Gelbard, Sarah Abou Alaiwi, Ji-Heui Seo, Justin H. Hwang, Craig A. Strathdee, Sylvan C. Baca, Jiao Li, Shatha AbuHammad, Xiaoyang Zhang, John G. Doench, William C. Hahn, David Y. Takeda, Matthew L. Freedman, View ORCID ProfilePeter S. Choi, View ORCID ProfileSrinivas R. Viswanathan
doi: https://doi.org/10.1101/2020.06.17.156034
Stephen Tang
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
2Broad Institute of MIT and Harvard, Cambridge, MA 02142
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Nebiyou Y. Metaferia
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
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Marina F. Nogueira
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
2Broad Institute of MIT and Harvard, Cambridge, MA 02142
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Maya K. Gelbard
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
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Sarah Abou Alaiwi
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
3Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215
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Ji-Heui Seo
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
3Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215
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Justin H. Hwang
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
2Broad Institute of MIT and Harvard, Cambridge, MA 02142
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Craig A. Strathdee
2Broad Institute of MIT and Harvard, Cambridge, MA 02142
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Sylvan C. Baca
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
2Broad Institute of MIT and Harvard, Cambridge, MA 02142
3Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215
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Jiao Li
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
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Shatha AbuHammad
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
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Xiaoyang Zhang
4Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112
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John G. Doench
2Broad Institute of MIT and Harvard, Cambridge, MA 02142
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William C. Hahn
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
2Broad Institute of MIT and Harvard, Cambridge, MA 02142
5Harvard Medical School, Boston, MA 02215
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David Y. Takeda
6Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892
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Matthew L. Freedman
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
2Broad Institute of MIT and Harvard, Cambridge, MA 02142
3Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215
5Harvard Medical School, Boston, MA 02215
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Peter S. Choi
7Division of Cancer Pathobiology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104
8Department of Pathology & Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104
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  • For correspondence: peter.choi@pennmedicine.upenn.edu srinivas.viswanathan@dfci.harvard.edu
Srinivas R. Viswanathan
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215
2Broad Institute of MIT and Harvard, Cambridge, MA 02142
5Harvard Medical School, Boston, MA 02215
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  • For correspondence: peter.choi@pennmedicine.upenn.edu srinivas.viswanathan@dfci.harvard.edu
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ABSTRACT

Androgen receptor (AR) signaling is the central driver of prostate cancer growth and progression across disease states, including in most cases of castration-resistant prostate cancer (CRPC). While next-generation AR antagonists and androgen synthesis inhibitors are effective for a time in CRPC, tumors invariably develop resistance to these agents, commonly through mechanisms resulting in the overexpression of AR or the production of constitutively active AR splice variants (e.g. AR-V7). Improved mechanistic understanding of the factors that modulate AR expression and signaling may reveal additional therapeutic intervention points in CRPC. Here, we leverage genome-scale CRISPR/Cas9 genetic screening to systematically identify regulators of AR/AR-V7 expression. We identify protein arginine methyltransferase 1 (PRMT1) as a critical mediator of AR expression and signaling that regulates recruitment of AR to genomic target sites. PRMT1 suppression globally perturbs the expression and splicing of AR target genes and inhibits the proliferation and survival of AR-positive prostate cancer cells. Genetic or pharmacologic inhibition of PRMT1 reduces AR binding at lineage-specific enhancers, which leads to decreased expression of key oncogenes, including AR itself. CRPC cells displaying activated AR signaling due to overexpression of AR or AR-V7 are uniquely susceptible to combined AR and PRMT1 inhibition. Our findings implicate PRMT1 as a critical regulator of AR output and provide a preclinical framework for co-targeting of AR and PRMT1 as a promising new therapeutic strategy in CRPC.

Competing Interest Statement

J.G.D. consults for Tango Therapeutics, Maze Therapeutics, Foghorn Therapeutics, and Pfizer. W.C.H. is a consultant for ThermoFisher, Solvasta Ventures, MPM Capital, KSQ Therapeutics, iTeos, Tyra Biosciences, Jubilant Therapeutics, Frontier Medicine and Parexel.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Genome-scale genetic screening identifies PRMT1 as a critical vulnerability in castration-resistant prostate cancer
Stephen Tang, Nebiyou Y. Metaferia, Marina F. Nogueira, Maya K. Gelbard, Sarah Abou Alaiwi, Ji-Heui Seo, Justin H. Hwang, Craig A. Strathdee, Sylvan C. Baca, Jiao Li, Shatha AbuHammad, Xiaoyang Zhang, John G. Doench, William C. Hahn, David Y. Takeda, Matthew L. Freedman, Peter S. Choi, Srinivas R. Viswanathan
bioRxiv 2020.06.17.156034; doi: https://doi.org/10.1101/2020.06.17.156034
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Genome-scale genetic screening identifies PRMT1 as a critical vulnerability in castration-resistant prostate cancer
Stephen Tang, Nebiyou Y. Metaferia, Marina F. Nogueira, Maya K. Gelbard, Sarah Abou Alaiwi, Ji-Heui Seo, Justin H. Hwang, Craig A. Strathdee, Sylvan C. Baca, Jiao Li, Shatha AbuHammad, Xiaoyang Zhang, John G. Doench, William C. Hahn, David Y. Takeda, Matthew L. Freedman, Peter S. Choi, Srinivas R. Viswanathan
bioRxiv 2020.06.17.156034; doi: https://doi.org/10.1101/2020.06.17.156034

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