SFK Inhibitors as New Strategy for RMS Treatment Luigi Bagella 1,2* and Irene Marchesi 1 Department of Biomedical Sciences, and National Institute of Biostructures and Biosystems, University of Sassari, Sassari, Italy 2 Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia USA *Corresponding author: Luigi Bagella, Adjunct Associate Professor Sbarro Health Research Organization Center of Biotechnology Deptartment of Biology College of Science and Technology, Temple University, BioLife Science Building, Philadelphia, USA, Tel: 215-204-9524; Fax: 215-204-9522; E-mail: bagella@temple.edu Received date: January 07, 2016; Accepted date: February 11, 2016; Published date: February 16, 2016 Copyright: © 2016 Bagella L, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction A new study investigates about the activity of a new SFK inhibitor in RMS. SI221 is a pyrazolo [3,4-d] pyrimidine derivative able to reduce both apoptosis and diferentiation in eRMS and aRMS. SFKs are frequently overexpressed in RMS and their inhibition can be a good strategy for RMS treatment. Rhabdomyosarcoma (RMS) represents approximately half of the total pediatric sof tissue sarcoma (STS), slightly more frequent in males but equally distributed across racial groups [1]. RMS is characterized by the expression of genes involved in the early myogenesis which fail to complete diferentiation and cell cycle arrest [2]. It can be divided into 2 major histological subtypes: embryonal (eRMS), mostly found in childhood, and alveolar (aRMS) common in both children and adults [1]. Te outcome of RMS patients is improved in the last decades (5- year survival rates of ~70%), however, patients with tumor relapse afer treatment or with metastasis at diagnosis are rarely cured [3,4]. Moreover, frequent toxicity and long-term side efects associated with the therapy, dramatically afect the quality of life [1]. Consequently, new specifc therapeutic strategies, able to reduce toxicity and side efects, are required for the treatment of RMS. Te induction of diferentiation and/or cell death through the inhibition of specifc enzyme involved in carcinogenesis and tumor progression can be a promising strategy for RMS patients. For instance, several studies focus on the role of epigenetic changes in RMS with the purpose to investigate if the modulation of the activity of some epigenetic enzyme can help to induce apoptosis or diferentiation in RMS cells [5-8]. Recently, Casini and coworkers analyzed efects of a new SRC family kinase (SFK) inhibitor in RMS. Tis molecule called SI221 is a pyrazolo [3,4-d] pyrimidine derivative that showed an antiproliferative and pro-apoptotic activity in several tumors [9-11]. Casini et al., demonstrated that SI221 specifcally inhibited SFKs and in particular YES, a SKK member that have an oncogenic role in eRMS and aRMS (described below) [12]. SI221 was able to induce apoptosis, to reduce cell migration and invasion with low cytotoxic efects on normal cells. Moreover, treated cells showed a partial rescue of muscular phenotype and an increase of myogenic markers. Tese efects were dependent by the activation of p38 pathway [13]. SFK is a family of non-receptor tyrosine kinases that includes c- SRC, FYN, YES, BLK, YRK, FGR, HCK, LCK and LYN. Tese enzymes are involved in several biological processes as cell proliferation, adhesion, invasion and motility; their expression or activity is frequently altered in cancer [14]. SKFs modulate adhesion, invasion and cell motility mainly through the disruption of adherents and focal junctions. Adherent junctions are responsible for cell–cell adhesion and they are composed by E-cadherin homodimers of adjacent cells connected to the actin cytoskeleton through the complex α-catenin-β-catenin and p120 catenin. c-SRC activated by protein tyrosine phosphatase 1B- dependent de-phosphorylation, associates to this complex promoting the disassembly of adherents junction. Focal adhesions are responsible for the binding of cells to the extracellular matrix through heterodimers α- and β-integrin. A cytoplasmic complex connects integrins to the cytoskeleton. SFKs activate focal-adhesion kinase (FAK) that in turn phosphorylate several component of the junctions promoting cytoskeleton changes and focal adhesion disruption (reviewed in [14]). Furthermore, c-SRC induces tyrosine phosphorylation of RRAS, suppressing integrin activity, cell-matrix adhesion and disrupting focal adhesion [15] Moreover, SFKs induce phosphorylation, ubiquitylation and endocytosis of E-cadherin, promoting the release of cells from the matrix and from each other [16]. Several papers explore the role of SFK and associated pathways in sarcomas. A frst screening showed that SRC is activated in human sarcomas and sarcoma cell lines [17]. Moreover, global tyrosine phosphorylation analysis in sarcoma cell lines and human tumor samples showed an increase of the expression and phosphorylation of tyrosine kinases including several members of SFKs as, for instance, c-SRC, LYN, and FAK [18]. Furthermore, the treatment of several sarcoma cell lines with Dasatinib, a SFK inhibitor, blocks SRC downstream pathways inhibiting FAK and p130cas signaling. Dasatinib inhibited cell motility and invasion, indicating SFKs as good targets for sarcoma treatment [17] (Table 1). Clinical phase (ClinicalTrials.gov) Dasatinibi b eRMS, aRMS Phase 1/2 for several tumors, also in combination with other drugs PP2 eRMS, aRMS Preclinical Saracatini b eRMS, aRMS Phase 2/3 for several tumors Phase 2 for RMS (Adult) SI221 eRMS, aRMS Preclinical Table 1: SFK inhibitors tested in RMS. For what concern specifcally RMS, it has been shown that SFKs have a role in both eRMS and aRMS. For instance, SFC increases oncogenic activity of Caveolin-1 through its phosphorylation Bagella and Marchesi, Chemo Open Access 2016, 5:2 DOI: 10.4172/2167-7700.1000189 Short Communication Open Access Chemo Open Access ISSN:2167-7700 CMT, an Open Access Journal Volume 5 • Issue 2 • 1000189 C h e m o t h er a p y : O p en A c c e s s ISSN: 2167-7700 Chemotherapy: Open Access