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Cancer Res. 2015 Jan 1;75(1):230-40. doi: 10.1158/0008-5472.CAN-14-0629. Epub 2014 Nov 11.

SYK is a candidate kinase target for the treatment of advanced prostate cancer.

Author information

1
Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
2
Department of Molecular Cell Biology, Institute of Biology, Leiden University, Leiden, the Netherlands.
3
Department of Urology, Leiden University Medical Center, Leiden, the Netherlands.
4
Galapagos BV, Leiden, the Netherlands.
5
Department of Urology, Erasmus University Medical Center, Rotterdam, the Netherlands.
6
Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands.
7
Department of Molecular Cell Biology, Institute of Biology, Leiden University, Leiden, the Netherlands. e.danen@lacdr.leidenuniv.nl b.e.snaar-jagalska@biology.leidenuniv.nl.
8
Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands. e.danen@lacdr.leidenuniv.nl b.e.snaar-jagalska@biology.leidenuniv.nl.

Abstract

Improved targeted therapies are needed to combat metastatic prostate cancer. Here, we report the identification of the spleen kinase SYK as a mediator of metastatic dissemination in zebrafish and mouse xenograft models of human prostate cancer. Although SYK has not been implicated previously in this disease, we found that its expression is upregulated in human prostate cancers and associated with malignant progression. RNAi-mediated silencing prevented invasive outgrowth in vitro and bone colonization in vivo, effects that were reversed by wild-type but not kinase-dead SYK expression. In the absence of SYK expression, cell surface levels of the progression-associated adhesion receptors integrin α2β1 and CD44 were diminished. RNAi-mediated silencing of α2β1 phenocopied SYK depletion in vitro and in vivo, suggesting an effector role for α2β1 in this setting. Notably, pharmacologic inhibitors of SYK kinase currently in phase I-II trials for other indications interfered similarly with the invasive growth and dissemination of prostate cancer cells. Our findings offer a mechanistic rationale to reposition SYK kinase inhibitors for evaluation in patients with metastatic prostate cancer.

PMID:
25388286
DOI:
10.1158/0008-5472.CAN-14-0629
[Indexed for MEDLINE]
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