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

Journal article
Authors M. Trautmann
M. Cyra
I. Isfort
B. Jeiler
A. Kruger
I. Grunewald
K. Steinestel
B. Altvater
C. Rossig
S. Hafner
T. Simmet
J. Becker
Pierre Åman
E. Wardelmann
S. Huss
W. Hartmann
Published in Molecular Cancer Therapeutics
Volume 18
Issue 4
Pages 834-844
ISSN 1535-7163
Publication year 2019
Published at Sahlgrenska Cancer Center
Pages 834-844
Language en
Links dx.doi.org/10.1158/1535-7163.Mct-18...
Keywords chop fusion protein, dermatofibrosarcoma protuberans, therapeutic, target, in-vitro, growth, inhibition, pathway, cells, gene, expression
Subject categories Cancer and Oncology

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 MIS and the potential of PI3Kdirected therapeutic concepts. In a large cohort of MIS, key components of the PI3K/Akt signaling cascade were evaluated by next generation seqeuncing (NGS), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC). In threevi IS cell lines, PI3K activitywas inhibited by RNAi and the small-molecule PI3 K 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 MIS, implying alternative mechanisms of pathway activation. P13K-directed therapeutic interference showed that MIS cell proliferation and viability significantly depended on PI3K-mediated signals in vitro and in viva Our predinical 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 P13K/Akt signaling components.

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