Mutationally activated kinases play an important role in the progression and metastasis of many cancers. Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations of kinases are rare. Several lines of evidence suggest that nonmutated kinases and their pathways are involved in prostate cancer progression, but few kinases have been mechanistically linked to metastasis. Using a mass spectrometry-based phosphoproteomics dataset in concert with gene expression analysis, we selected over 100 kinases potentially implicated in human metastatic prostate cancer for functional evaluation. A primary in vivo screen based on overexpression of candidate kinases in murine prostate cells identified 20 wild-type kinases that promote metastasis. We queried these 20 kinases in a secondary in vivo screen using human prostate cells. Strikingly, all three RAF family members, MERTK, and NTRK2 drove the formation of bone and visceral metastasis confirmed by positron-emission tomography combined with computed tomography imaging and histology. Immunohistochemistry of tissue microarrays indicated that these kinases are highly expressed in human metastatic castration-resistant prostate cancer tissues. Our functional studies reveal the strong capability of select wild-type protein kinases to drive critical steps of the metastatic cascade, and implicate these kinases in possible therapeutic intervention.
|Original language||English (US)|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Jan 12 2016|
Bibliographical noteFunding Information:
We thank members of the O.N.W. laboratory for helpful comments and discussion. We are grateful to the patients and their families who were willing to participate in the University of Washington''s Prostate Cancer Donor Program and the investigators Drs. Robert Vessella, Celestia Higano, Bruce Montgomery, Evan Yu, Peter Nelson, Paul Lange, Martine Roudier, and Lawrence True and the Rapid Autopsy team for their contributions to the University of Washington Medical Center Prostate Cancer Donor Rapid Autopsy Program. This research was supported by funding from the Pacific Northwest Prostate Cancer Specialized Program of Research Excellence (SPORE) (P50CA97186) and a P01 NIH grant (P01CA085859). We thank Dr. Daniel Margolis for radiological evaluation of PET/CT scans; UCLA Molecular Imaging Center and staff; H. Wu laboratory for cell lines; UCLA Translational Pathology Core Laboratory for assistance with tissue processing and H&E staining; and Donghui Cheng for help with FACS sorting. C.M.F. was supported by a California Institute of Regenerative Medicine Training Grant (TG2-01169) and USHHS Ruth L. Kirschstein Institutional National Research Service Award (T32 CA009056); J.M.D. was supported by the Department of Defense Prostate Cancer Research Program (W81XWH-14-1-0148); P.M.C. was supported by a California Institute of Regenerative Medicine Training Grant (TG2-01169), UCLA Scholars in Oncologic Molecular Imaging Program National Cancer Institute Grant (R25T CA098010), and UCLA in Vivo Cellular and Molecular Imaging Center Career Development Award (P50 CA086306); and B.A.S. was supported by a UCLA Tumor Immunology Training Grant (T32 CA00912). J.H. is supported by NIH Grants 5R01CA172603-02 [principal investigator (PI): J.H.], 2P30CA016042-39 (PI: Judith Gasson), 1R01CA181242-01A1 (PI: Chun Chao), and 1R01CA195505 (PI: Leonard Marks); Department of Defense Prostate Cancer Research Program W81XWH-12-1-0206 (PI: Lily Wu); UCLA SPORE in prostate cancer (PI: Robert Reiter); Prostate Cancer Foundation Honorable A. David Mazzone Special Challenge Award (PI: Robert Reiter); and UCLA Jonsson Comprehensive Cancer Center Impact Grant (PI: Sanaz Memarzadeh). O.N.W. is an Investigator of the Howard Hughes Medical Institute and is supported by a Prostate Cancer Foundation Challenge Award. J.H. and O.N.W. are supported by a Stand Up To Cancer-Prostate Cancer Foundation Prostate Dream Team Translational Research Grant (SU2C-AACR-DT0812). This research grant is made possible by the generous support of the Movember Foundation. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.
- Bone metastasis
- Prostate cancer