Abstract 2855: SRC represents a potential therapeutic target in liposarcoma

Abstract

Abstract Liposarcomas (LS) represent the most common malignant soft tissue tumors in adults. Therapeutic outcome of LS is mainly determined by the efficiency of surgery as a high tendency for local relapse is seen. Chemo- and radiotherapy represent further therapeutic options, however, specifically targeted therapies are currently not available. The oncoprotein SRC is a tyrosine kinase, which has been shown to be activated in a variety of human cancers. SRC activation plays an important role in cancer cell proliferation, survival, angiogenesis and motility. In this work we analyzed LS biopsies comprising the main different subgroups, i.e. myxoid (MLS), well/dedifferentiated (WDLS/DDLS) and pleomorphic (PLS) LS and corresponding cell lines regarding SRC activation and studied the biological effects of SRC inhibition. Based on data derived from phospho-kinase screens in LS cells, immunhistochemical stainings of (Tyr416)-phosphorylated (p)-SRC were performed in primary LS biopsies. LS cell lines treated with the SRC inhibitor dasatinib were analyzed for phosphorylation of SRC and its downstream signaling molecules, cell proliferation, migration and apoptosis. Furthermore, synergistic effects of simultaneous treatments with dasatinib and conventional cytotoxic drugs were investigated. Particularly WDLS/DDLS and MLS tumor cells showed a significant expression of p-SRC. In LS cell lines, inhibition of SRC with dasatinib resulted in a substantially impaired cellular growth accompanied by a decreased phosphorylation of SRC and its downstream targets. Flow cytometric analysis showed that effects of SRC inhibition were due to an increase in apoptosis (cleaved PARP(Asp 214)) and a decrease of cellular proliferation (phospho-(Ser10) Histone H3). Scratch and Boyden chamber assays indicated a diminished migratory potential of the tumor cells due to SRC inactivation. Simultaneous treatment of liposarcoma cell lines with dasatinib and chemotherapeutic drugs resulted in additive effects. Our data suggest that SRC kinase activation represents an important biological feature of LS which might be successfully addressed in targeted therapeutic approaches. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2855. doi:1538-7445.AM2012-2855