Abstract 3939: Activation of phosphatidylinositol-3′-kinase/Akt signaling in myxoid liposarcoma

Abstract

Abstract Introduction: Myxoid liposarcoma (MLS) is the second most common type of liposarcoma and characterized by a high tendency to develop metastases. The molecular hallmark of MLS (≈90%) is a pathognomonic reciprocal t(12;16) (q13;p11) translocation, leading to the specific gene fusion of FUS and DDIT3. The resulting chimeric FUS-DDIT3 fusion protein is suggested to play a crucial role in MLS tumorigenesis, although its specific biological function and mechanism of action remain to be substantiated. While radiotherapy and chemotherapy with high-dose ifosfamide and doxorubicin represent established therapeutic options, prognosis in the metastasized situation is poor. Molecularly targeted therapeutic approaches are currently not available. Aiming at the preclinical identification of novel therapeutic options, we here investigate the functional relevance of phosphatidylinositol-3'-kinase (PI3-kinase)/Akt signaling in MLS. Experimental procedures: Immunohistochemical and FISH analyses of PI3-kinase/Akt signaling effectors were performed in a large cohort of clinical MLS tumor specimens. Mutational burden was studied by targeted next-generation sequencing (NGS; Illumina MiSeq). PI3-kinase/Akt-mediated signaling transduction was modulated by specific RNAi knockdown and a pharmacological approach applying the small molecule inhibitor BKM120 (Buparlisib; NVP-BKM120). Cell proliferation and FACS assays were performed in different MLS cell lines. An established MLS chorioallantoic membrane model (CAM) was employed for in vivo confirmation of the preclinical in vitro data. Results: In a significant subset of MLS tumor specimens, immunohistochemical staining revealed elevated phosphorylation levels of various signaling components, indicating that activation of PI3-kinase/Akt signaling is a frequent feature in MLS. Activating PIK3CA mutations and loss of PTEN as mechanism for PI3-kinase/Akt activation were detected in ≈15%. PI3-kinase inhibition significantly suppressed the signaling cascade, associated with reduction of MLS cell viability and induction of apoptosis in vitro and in vivo. Conclusions: Our preclinical study emphasizes the pivotal role of the PI3-kinase/Akt signaling cascade in MLS pathogenesis and indicates the occurrence of specific mutational aberrations apart from the pathognomonic FUS-DDIT3 gene fusion. Our in vitro and in vivo results suggest that targeting the PI3-kinase/Akt signaling pathway provides a rational, molecularly founded therapeutic strategy in the treatment of MLS. Citation Format: Marcel Trautmann, Magdalene Cyra, Christian Bertling, Ilka Isfort, Bianca Altvater, Claudia Rossig, Susanne Hafner, Thomas Simmet, Jessica Becker, Inga Grünewald, Pierre Åman, Reinhard Büttner, Eva Wardelmann, Sebastian Huss, Wolfgang Hartmann. Activation of phosphatidylinositol-3′-kinase/Akt signaling in myxoid liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3939.