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. NelsonLeigh Ellis, Justin M. Drake

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1176-1188
Number of pages13
JournalMolecular Cancer Research
Volume18
Issue number8
DOIs
StatePublished - Aug 1 2020

Bibliographical note

Funding Information:
the Development of the LuCaP PDX models. H.R. VanDeusen is supported by Department of Defense Prostate Cancer Research Program W81XWH-19-1-0173. This work was also supported by the Department of Defense grant (W81XWH-17-1-0414; W81XWH-17-1-0415; W81XWH-18-1-0347), the Prostate Cancer Biorepo-sitory Network (PCBN; W81XWH-14-2-0183), the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the PO1 NIH grant (PO1 CA163227), the Richard M. LUCAS Foundation, and the Institute for Prostate Cancer Research (IPCR). L.C. Cheng and V.M. Tan are supported by the National Institute of General Medical Sciences of the NIH under award number T32 GM008339. J.W. Park is supported by the NIH/NCI grant K99/R00 Pathway to Independence award K99CA218731/ R00CA218731. R. Yang is supported by Department of Defense Prostate Cancer Research Program W81XWH-19-1-0161. J.H. Hwang is supported by American Cancer Society-AstraZeneca (PF-16-142-01-TBE). O.N. Witte is supported by the Zimmerman Family, the Concern Foundation, and by a Prostate Cancer Foundation Challenge Award. O.N. Witte is also supported by the West Coast Prostate Cancer Dream Team supported by a Stand Up to Cancer-Prostate Cancer Foundation-Prostate Cancer Dream Team Translational Cancer Research Grant (SU2C-AACR-DT0812; co-principal investigator: O.N. Witte). This research grant is made possible

Funding Information:
We thank members of the Drake lab for providing advice and input on the manuscript. We also thank the members of the Biological Mass Spectrometry Facility of Robert Wood Johnson Medical School and Rutgers, The State University of New Jersey, for providing advice and performing mass spectrometry on our samples. We thank Ryder Clifford from QGel for providing reagents. We thank the patients and their families, Celestia Higano, Evan Yu, Elahe Mostaghel, Heather Cheng, Bruce Montgomery, Mike Schweizer, Andrew Hsieh, Daniel Lin, Funda Vakar-Lopez, Lawrence True and the rapid autopsy teams for their contributions to the University of Washington Medical Center Prostate Cancer Donor Rapid Autopsy Program and the Development of the LuCaP PDX models. H.R. VanDeusen is supported by Department of Defense Prostate Cancer Research Program W81XWH-19-1-0173. This work was also supported by the Department of Defense grant (W81XWH-17-1-0414; W81XWH-17-1-0415; W81XWH-18-1-0347), the Prostate Cancer Biorepository Network (PCBN; W81XWH-14-2-0183), the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the PO1 NIH grant (PO1 CA163227), the Richard M. LUCAS Foundation, and the Institute for Prostate Cancer Research (IPCR). L.C. Cheng and V.M. Tan are supported by the National Institute of General Medical Sciences of the NIH under award number T32 GM008339. J.W. Park is supported by the NIH/NCI grant K99/R00 Pathway to Independence award K99CA218731/ R00CA218731. R. Yang is supported by Department of Defense Prostate Cancer Research Program W81XWH-19-1-0161. J.H. Hwang is supported by American Cancer Society-AstraZeneca (PF-16-142-01-TBE). O.N. Witte is supported by the Zimmerman Family, the Concern Foundation, and by a Prostate Cancer Foundation Challenge Award. O.N. Witte is also supported by the West Coast Prostate Cancer Dream Team supported by a Stand Up to Cancer-Prostate Cancer Foundation-Prostate Cancer Dream Team Translational Cancer Research Grant (SU2C-AACRDT0812; co-principal investigator: O.N. Witte). This research grant is made possible by the generous support of the Movember Foundation. Stand Up To Cancer is a division of the Entertainment Industry Foundation. The research grant is administered by the American Association for Cancer Research. L. Ellis is supported by the Department of Defense Prostate Cancer Research Program W81XWH-18-1-0541. J. M. Drake is supported by the Department of Defense Prostate Cancer Research Program W81XWH-14-1-0148, W81XWH-15-1-0236 and W81XWH-18-1-0542, Prostate Cancer Foundation Young Investigator Award, and the New Jersey Health Foundation. Research reported in this publication was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1-TR002494.

Publisher Copyright:
© 2020 American Association for Cancer Research.

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