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

被引:27
|
作者
Trautmann, Marcel [1 ,2 ]
Cyra, Magdalene [1 ,2 ]
Isfort, Ilka [1 ,2 ]
Jeiler, Birte [1 ,2 ]
Krueger, Arne [1 ,2 ]
Gruenewald, Inga [1 ,2 ]
Steinestel, Konrad [1 ,3 ]
Altvater, Bianca [4 ]
Rossig, Claudia [4 ,5 ]
Hafner, Susanne [6 ]
Simmet, Thomas [6 ]
Becker, Jessica [7 ,8 ]
Amana, Pierre [9 ]
Wardelmann, Eva [1 ]
Huss, Sebastian [1 ]
Hartmann, Wolfgang [1 ,2 ]
机构
[1] Munster Univ Hosp, Gerhard Domagk Inst Pathol, Munster, Germany
[2] Munster Univ Hosp, Gerhard Domagk Inst Pathol, Div Translat Pathol, Domagkstr 17, D-48149 Munster, Germany
[3] Bundeswehrkrankenhaus Ulm, Inst Pathol & Mol Pathol, Ulm, Germany
[4] Univ Childrens Hosp Munster, Dept Pediat Hematol & Oncol, Munster, Germany
[5] Univ Munster, Cells Mot Cluster Excellence EXC CiM 1003, Munster, Germany
[6] Ulm Univ, Inst Pharmacol Nat Prod & Clin Pharmacol, Ulm, Germany
[7] Univ Bonn, Inst Human Genet, Sch Med, Bonn, Germany
[8] Univ Bonn, Univ Hosp Bonn, Bonn, Germany
[9] Univ Gothenburg, Sahlgrenska Canc Ctr, Gothenburg, Sweden
关键词
CHOP FUSION PROTEIN; DERMATOFIBROSARCOMA PROTUBERANS; THERAPEUTIC TARGET; IN-VITRO; GROWTH; INHIBITION; PATHWAY; CELLS; GENE; EXPRESSION;
D O I
10.1158/1535-7163.MCT-18-0763
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:834 / 844
页数:11
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