Functional screen identifies kinases driving prostate cancer visceral and bone metastasis.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Faltermeier, CM; Drake, JM; Clark, PM; Smith, BA; Zong, Y; Volpe, C; Mathis, C; Morrissey, C; Castor, B; Huang, J; Witte, ON
Published Date
- January 12, 2016
Published In
Volume / Issue
- 113 / 2
Start / End Page
- E172 - E181
PubMed ID
- 26621741
Pubmed Central ID
- PMC4720329
Electronic International Standard Serial Number (EISSN)
- 1091-6490
Digital Object Identifier (DOI)
- 10.1073/pnas.1521674112
Language
- eng
Conference Location
- United States