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Molecular Cancer Research
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Signal Transduction and Functional Imaging

Targeting RET Kinase in Neuroendocrine Prostate Cancer

Halena R. VanDeusen, Johnny R. Ramroop, Katherine L. Morel, Song Yi Bae, Anjali V. Sheahan, Zoi Sychev, Nathan A. Lau, Larry C. Cheng, Victor M. Tan, Zhen Li, Ashley Petersen, John K. Lee, Jung Wook Park, Rendong Yang, Justin H. Hwang, Ilsa Coleman, Owen N. Witte, Colm Morrissey, Eva Corey, Peter S. Nelson, Leigh Ellis and Justin M. Drake
Halena R. VanDeusen
1Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, Minnesota.
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  • ORCID record for Halena R. VanDeusen
Johnny R. Ramroop
2Departments of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
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Katherine L. Morel
3Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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  • ORCID record for Katherine L. Morel
Song Yi Bae
1Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, Minnesota.
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Anjali V. Sheahan
3Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Zoi Sychev
1Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, Minnesota.
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Nathan A. Lau
4Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
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Larry C. Cheng
5Graduate Program in Quantitative Biomedicine, School of Graduate Studies, Rutgers University, New Brunswick, New Jersey.
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Victor M. Tan
5Graduate Program in Quantitative Biomedicine, School of Graduate Studies, Rutgers University, New Brunswick, New Jersey.
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Zhen Li
6Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
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  • ORCID record for Zhen Li
Ashley Petersen
7Division of Biostatistics, School of Public Health, University of Minnesota-Twin Cities, Minneapolis, Minnesota.
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John K. Lee
4Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
8Department of Medicine, University of Washington, Seattle, Washington.
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Jung Wook Park
9Department of Pathology, Duke School of Medicine, Duke University, Durham, North Carolina.
10Department of Microbiology, Immunology, and Molecular Genetics, University of California–Los Angeles, Los Angeles, California.
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Rendong Yang
11The Hormel Institute, University of Minnesota, Austin, Minnesota.
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Justin H. Hwang
12Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
13Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
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Ilsa Coleman
4Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
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Owen N. Witte
10Department of Microbiology, Immunology, and Molecular Genetics, University of California–Los Angeles, Los Angeles, California.
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Colm Morrissey
14Department of Urology, University of Washington, Seattle, Washington.
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Eva Corey
14Department of Urology, University of Washington, Seattle, Washington.
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Peter S. Nelson
4Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
8Department of Medicine, University of Washington, Seattle, Washington.
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Leigh Ellis
3Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
13Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
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Justin M. Drake
1Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, Minnesota.
15Department of Urology, University of Minnesota-Twin Cities, Minneapolis, Minnesota.
16Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, Minnesota.
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  • For correspondence: jdrake@umn.edu
DOI: 10.1158/1541-7786.MCR-19-1245 Published August 2020
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Abstract

The increased treatment of metastatic castration-resistant prostate cancer (mCRPC) with second-generation antiandrogen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost dependence on androgen receptor (AR) signaling. These AR-independent tumors may also transdifferentiate to express neuroendocrine lineage markers and are termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing several AR-independent to AR-dependent prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-independent cell lines. Clinical NEPC patient samples and NEPC patient-derived xenografts displayed upregulated RET transcript and RET pathway activity. Genetic knockdown or pharmacologic inhibition of RET kinase in multiple mouse and human models of NEPC dramatically reduced tumor growth and decreased cell viability. Our results suggest that targeting RET in NEPC tumors with high RET expression could be an effective treatment option. Currently, there are limited treatment options for patients with aggressive neuroendocrine prostate cancer and none are curative.

Implications: Identification of aberrantly expressed RET kinase as a driver of tumor growth in multiple models of NEPC provides a significant rationale for testing the clinical application of RET inhibitors in patients with AVPC.

This article is featured in Highlights of This Issue, p. 1111

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2020;18:1176–88

  • Received December 23, 2019.
  • Revision received April 1, 2020.
  • Accepted May 19, 2020.
  • Published first May 27, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 18 (8)
August 2020
Volume 18, Issue 8
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Targeting RET Kinase in Neuroendocrine Prostate Cancer
Halena R. VanDeusen, Johnny R. Ramroop, Katherine L. Morel, Song Yi Bae, Anjali V. Sheahan, Zoi Sychev, Nathan A. Lau, Larry C. Cheng, Victor M. Tan, Zhen Li, Ashley Petersen, John K. Lee, Jung Wook Park, Rendong Yang, Justin H. Hwang, Ilsa Coleman, Owen N. Witte, Colm Morrissey, Eva Corey, Peter S. Nelson, Leigh Ellis and Justin M. Drake
Mol Cancer Res August 1 2020 (18) (8) 1176-1188; DOI: 10.1158/1541-7786.MCR-19-1245

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Targeting RET Kinase in Neuroendocrine Prostate Cancer
Halena R. VanDeusen, Johnny R. Ramroop, Katherine L. Morel, Song Yi Bae, Anjali V. Sheahan, Zoi Sychev, Nathan A. Lau, Larry C. Cheng, Victor M. Tan, Zhen Li, Ashley Petersen, John K. Lee, Jung Wook Park, Rendong Yang, Justin H. Hwang, Ilsa Coleman, Owen N. Witte, Colm Morrissey, Eva Corey, Peter S. Nelson, Leigh Ellis and Justin M. Drake
Mol Cancer Res August 1 2020 (18) (8) 1176-1188; DOI: 10.1158/1541-7786.MCR-19-1245
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