Abstract 3459: SRC family kinase FYN promotes MET tyrosine kinase activation, epithelial to mesenchymal transition and metastasis in human prostate cancer
Authors: Gururajan Murali , Sievert Margarit , Mink Sheldon , Chu Chia-Yi (Gina) , Morello Matteo , Lichterman Jake , Freeman Michael R. , Posadas Edwin M. 
Published: May 2015

Abstract
Introduction: FYN is a Src family kinase (SFK) member that has been shown to be upregulated in human prostate cancer tissues and cell lines (PCa). The majority of the studies on SRC kinases have focused on the classical c-SRC. We demonstrated previously that knockdown of FYN in PCa cell lines leads to reduced tumor growth in vitro and in vivo. We hypothesized that MET, an oncogenic tyrosine kinase receptor implicated in metastasis and therapeutic resistance of a variety of solid tumors is regulated by FYN expression in prostate cancer.
Methods: We performed in vitro growth assays, migration and invasion assays and studied PCa cell response to HGF in wildtype, FYN-depleted and FYN-reconstituted cells. Additionally, we studied the role of FYN in promoting metastasis in vivo in xenograft mouse models.
Summary: In this study, we demonstrate that knockdown of FYN leads to reduced migration, invasion and metastatic dissemination of PCa cells in vitro and in vivo. Conversely, ectopic expression of FYN promotes enhanced tumor growth and invasion. Hepatocyte growth factor (HGF) induced activation of MET is perturbed in FYN knockdown cells and overexpression of FYN leads to excessive MET activation suggesting a possible feedback loop between FYN and MET in prostate cancer. Consistent these findings, PC3 prostate cancer cells overexpressing FYN are resistant to treatment with a MET inhibitor upon ligand stimulation. More importantly, we show that FYN promotes epithelial to mesenchymal transition (EMT) of PCa cells and knockdown of FYN leads to reversal of EMT and alters radiation sensitivity of PCa cells. To further identify the molecular mechanism of FYN mediated regulation of tumor growth, we performed integrated RNA sequencing analysis of FYN knockdown cells and found MET and a network of molecular targets that appear to regulate FYN mediated tumor progression and metastasis.
Conclusions: We demonstrate that FYN mediated MET activation promotes PCa invasion, EMT and metastasis. None of the SFK inhibitors currently in clinical trials are specific for SFKs alone. Therefore, it is imperative to develop and test novel inhibitors that selectively target FYN and other SFKs. Our findings have therapeutic implications since clinical trials are being performed for both SFK inhibitors and MET inhibitors in castration resistant PCa patients. Our studies reveal that FYN and MET interact in PCa cells and this interaction is clinically relevant given the success of XL-184 (a MET inhibitor) in phase III clinical trials in human prostate cancer. Clinical studies with translational endpoints are the need of the hour with agents that effectively inhibit FYN and MET in a variety of settings.
Citation Format: Murali Gururajan, Margarit Sievert, Sheldon Mink, Chia-Yi (Gina) Chu, Matteo Morello, Jake Lichterman, Michael R. Freeman, Edwin M. Posadas. SRC family kinase FYN promotes MET tyrosine kinase activation, epithelial to mesenchymal transition and metastasis in human prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3459. doi:10.1158/1538-7445.AM2014-3459