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

• Published in: Cancer research (Chicago, Ill.) Vol. 75; no. 1; pp. 230 - 240
• Main Authors: Ghotra, Veerander P S, He, Shuning, van der Horst, Geertje, Nijhoff, Steffen, de Bont, Hans, Lekkerkerker, Annemarie, Janssen, Richard, Jenster, Guido, van Leenders, Geert J L H, Hoogland, A Marije M, Verhoef, Esther I, Baranski, Zuzanna, Xiong, Jiangling, van de Water, Bob, van der Pluijm, Gabri, Snaar-Jagalska, B Ewa, Danen, Erik H J
• Format: Journal Article
• Language: English
• Published: United States 01.01.2015
• Subjects: Animals; Cell Line, Tumor; HEK293 Cells; Heterografts; Humans; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - deficiency; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - deficiency; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; Syk Kinase; Zebrafish
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-14-0629

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.