Phosphatidylinositol-3-kinase (PI3K)/Akt signaling is functionally essential in myxoid liposarcoma

Trautmann M, Cyra M, Isfort I, Jeiler B, Krüger A, Grünewald I, Steinestel K, Altvater B, Rossig C, Hafner S

Abstract

Myxoid liposarcoma is an aggressive soft tissue tumor characterized by a specific reciprocal t(12;16) translocation resulting in expression of the chimeric FUS-DDIT3 fusion protein, an oncogenic transcription factor. Similar to other translocation‑associated sarcomas, myxoid liposarcoma are characterized by a low frequency of somatic mutations, albeit a subset of myxoid liposarcoma has previously been shown to be associated with activating PIK3CA mutations. The present study was performed to assess the prevalence of PI3K/Akt signaling alterations in myxoid liposarcoma and the potential of PI3K‑directed therapeutic concepts. In a large cohort of myxoid liposarcoma, key components of the PI3K/Akt signaling cascade were evaluated by next-generation sequencing, fluorescence in situ hybridization and immunohistochemistry. In three myxoid liposarcoma cell lines, PI3K activity was inhibited by RNAi and the small molecule PI3K inhibitor BKM120 (Buparlisib) in vitro. A myxoid liposarcoma cell line based avian chorioallantoic membrane model was applied for in vivo confirmation. In total, 26.8% of myxoid liposarcoma cases displayed activating alterations in PI3K/Akt signaling components, with PIK3CA gain-of-function mutations representing the most prevalent finding (14.2%). Immunohistochemistry pointed to PI3K/Akt activation in a far larger subgroup of myxoid liposarcoma, implying alternative mechanisms of pathway activation. PI3K‑directed therapeutic interference showed that myxoid liposarcoma cell proliferation and viability significantly depended on PI3K-mediated signals in vitro and in vivo. Our preclinical study underlines the elementary role of PI3K/Akt signals in myxoid liposarcoma tumorigenesis and provides a molecularly based rationale for a PI3K‑targeted therapeutic approach which may be particularly effective in tumors carrying activating genetic alterations in PI3K/Akt signaling components.