PMID- 30787173
OWN - NLM
STAT- MEDLINE
DCOM- 20200226
LR  - 20200930
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Linking)
VI  - 18
IP  - 4
DP  - 2019 Apr
TI  - Phosphatidylinositol-3-kinase (PI3K)/Akt Signaling is Functionally Essential in 
      Myxoid Liposarcoma.
PG  - 834-844
LID - 10.1158/1535-7163.MCT-18-0763 [doi]
AB  - 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.
CI  - (c)2019 American Association for Cancer Research.
FAU - Trautmann, Marcel
AU  - Trautmann M
AUID- ORCID: 0000-0002-5842-1196
AD  - Gerhard-Domagk-Institute of Pathology, Munster University Hospital, Munster, 
      Germany. marcel.trautmann@ukmuenster.de wolfgang.hartmann@ukmuenster.de.
AD  - Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, 
      Munster University Hospital, Munster, Germany.
FAU - Cyra, Magdalene
AU  - Cyra M
AD  - Gerhard-Domagk-Institute of Pathology, Munster University Hospital, Munster, 
      Germany.
AD  - Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, 
      Munster University Hospital, Munster, Germany.
FAU - Isfort, Ilka
AU  - Isfort I
AUID- ORCID: 0000-0002-7485-8769
AD  - Gerhard-Domagk-Institute of Pathology, Munster University Hospital, Munster, 
      Germany.
AD  - Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, 
      Munster University Hospital, Munster, Germany.
FAU - Jeiler, Birte
AU  - Jeiler B
AD  - Gerhard-Domagk-Institute of Pathology, Munster University Hospital, Munster, 
      Germany.
AD  - Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, 
      Munster University Hospital, Munster, Germany.
FAU - Kruger, Arne
AU  - Kruger A
AUID- ORCID: 0000-0002-5531-9508
AD  - Gerhard-Domagk-Institute of Pathology, Munster University Hospital, Munster, 
      Germany.
AD  - Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, 
      Munster University Hospital, Munster, Germany.
FAU - Grunewald, Inga
AU  - Grunewald I
AD  - Gerhard-Domagk-Institute of Pathology, Munster University Hospital, Munster, 
      Germany.
AD  - Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, 
      Munster University Hospital, Munster, Germany.
FAU - Steinestel, Konrad
AU  - Steinestel K
AD  - Gerhard-Domagk-Institute of Pathology, Munster University Hospital, Munster, 
      Germany.
AD  - Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, Ulm, 
      Germany.
FAU - Altvater, Bianca
AU  - Altvater B
AUID- ORCID: 0000-0003-4936-4879
AD  - Department of Pediatric Hematology and Oncology, University Children's Hospital 
      Munster, Munster, Germany.
FAU - Rossig, Claudia
AU  - Rossig C
AUID- ORCID: 0000-0002-8672-5285
AD  - Department of Pediatric Hematology and Oncology, University Children's Hospital 
      Munster, Munster, Germany.
AD  - Cells in Motion Cluster of Excellence (EXC 1003 - CiM), University of Munster, 
      Munster, Germany.
FAU - Hafner, Susanne
AU  - Hafner S
AD  - Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm 
      University, Ulm, Germany.
FAU - Simmet, Thomas
AU  - Simmet T
AD  - Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm 
      University, Ulm, Germany.
FAU - Becker, Jessica
AU  - Becker J
AD  - Institute of Human Genetics, School of Medicine & University Hospital Bonn, 
      University of Bonn, Bonn, Germany.
FAU - Aman, Pierre
AU  - Aman P
AUID- ORCID: 0000-0002-1482-8875
AD  - Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg, Sweden.
FAU - Wardelmann, Eva
AU  - Wardelmann E
AD  - Gerhard-Domagk-Institute of Pathology, Munster University Hospital, Munster, 
      Germany.
FAU - Huss, Sebastian
AU  - Huss S
AD  - Gerhard-Domagk-Institute of Pathology, Munster University Hospital, Munster, 
      Germany.
FAU - Hartmann, Wolfgang
AU  - Hartmann W
AD  - Gerhard-Domagk-Institute of Pathology, Munster University Hospital, Munster, 
      Germany. marcel.trautmann@ukmuenster.de wolfgang.hartmann@ukmuenster.de.
AD  - Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, 
      Munster University Hospital, Munster, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190220
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Aminopyridines)
RN  - 0 (Chromones)
RN  - 0 (Morpholines)
RN  - 0 (NVP-BKM120)
RN  - 0 (Oncogene Proteins, Fusion)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aminopyridines/pharmacology
MH  - Animals
MH  - Carcinogenesis/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Chick Embryo
MH  - Chorioallantoic Membrane/drug effects
MH  - Chromones/pharmacology
MH  - Class I Phosphatidylinositol 3-Kinases/antagonists & 
      inhibitors/*genetics/*metabolism
MH  - Cohort Studies
MH  - Female
MH  - Heterografts
MH  - Humans
MH  - Liposarcoma, Myxoid/*metabolism/pathology
MH  - Male
MH  - Middle Aged
MH  - Morpholines/pharmacology
MH  - Oncogene Proteins, Fusion/genetics
MH  - Proto-Oncogene Proteins c-akt/genetics/*metabolism
MH  - RNA Interference
MH  - Young Adult
EDAT- 2019/02/23 06:00
MHDA- 2020/02/27 06:00
CRDT- 2019/02/22 06:00
PHST- 2018/07/10 00:00 [received]
PHST- 2018/12/13 00:00 [revised]
PHST- 2019/01/28 00:00 [accepted]
PHST- 2019/02/23 06:00 [pubmed]
PHST- 2020/02/27 06:00 [medline]
PHST- 2019/02/22 06:00 [entrez]
AID - 1535-7163.MCT-18-0763 [pii]
AID - 10.1158/1535-7163.MCT-18-0763 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2019 Apr;18(4):834-844. doi: 10.1158/1535-7163.MCT-18-0763. Epub 
      2019 Feb 20.