Phosphatidylinositol-3-kinase (PI3K)/Akt Signaling is Functionally Essential in Myxoid Liposarcoma.

Marcel Trautmann,Eva Wardelmann,Susanne Hafner,Magdalene Cyra,Sebastian Huss,Ilka Isfort,Thomas Simmet,Arne Krüger,Bianca Altvater,Pierre Åman,Wolfgang Hartmann,Inga Grünewald,Jessica Becker,Claudia Rossig,Konrad Steinestel,Birte Jeiler

doi:10.1158/1535-7163.mct-18-0763

Abstract

Myxoid liposarcoma (MLS) 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, MLS is characterized by a low frequency of somatic mutations, albeit a subset of MLS has previously been shown to be associated with activating PIK3CA mutations. This study was performed to assess the prevalence of PI3K/Akt signaling alterations in MLS and the potential of PI3K-directed therapeutic concepts. In a large cohort of MLS, key components of the PI3K/Akt signaling cascade were evaluated by next generation seqeuncing (NGS), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). In three MLS cell lines, PI3K activity was inhibited by RNAi and the small-molecule PI3K inhibitor BKM120 (buparlisib) in vitro An MLS cell line-based avian chorioallantoic membrane model was applied for in vivo confirmation. In total, 26.8% of MLS cases displayed activating alterations in PI3K/Akt signaling components, with PIK3CA gain-of-function mutations representing the most prevalent finding (14.2%). IHC suggested PI3K/Akt activation in a far larger subgroup of MLS, implying alternative mechanisms of pathway activation. PI3K-directed therapeutic interference showed that MLS 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 MLS tumorigenesis and provides a molecularly based rationale for a PI3K-targeted therapeutic approach which may be particularly effective in the subgroup of tumors carrying activating genetic alterations in PI3K/Akt signaling components.

Highlights

Myxoid liposarcoma (MLS) accounts for approximately 5%–10% of all soft-tissue sarcomas, representing about 20% of all malignant adipocytic tumors [1]
It has been reported that EGFR, MET, VEGFR, RET, and PDGFRB signaling sustained by autocrine/paracrine transduction and receptor tyrosine kinase (RTK) cross-talk may lead to an increase in PI3Kdependent signals [16, 17]
Almost all MLS are characterized by a FUS-DDIT3 gene fusion, encoding an oncogenic transcription factor with the potential to transform mesenchymal stem cells to form MLS in mice [5]

Summary

Introduction

Myxoid liposarcoma (MLS) accounts for approximately 5%–10% of all soft-tissue sarcomas, representing about 20% of all malignant adipocytic tumors [1]. Previously published results indicate a fundamental relevance of PI3K/Akt signals with respect to the specific liability of MLS tumor cells, accomplished either by genetic PIK3CA and/or PTEN alterations or complex signaling networks [8, 12, 15,16,17, 22] resulting in aberrant activation of PI3K activity. This preclinical study was conducted to explore the functional importance of PI3K/ Akt signals in MLS tumorigenesis, and to establish a molecularly targeted strategy employing small-molecule PI3K inhibitors

Materials and Methods

Results

Discussion

Disclosure of Potential Conflicts of Interest