title: Hsp90 inhibition by AUY922 as an effective treatment strategy against myxoid liposarcoma.
abstract: Liposarcoma is one of the most common soft tissue sarcomas in adults. Recognized histological subtypes include well differentiated/dedifferentiated liposarcoma (WD/DDLS), myxoid liposarcoma (MLS) and pleomorphic liposarcoma. Currently, there are no proper subtype-specific treatments due to the genetic, histological and clinical heterogeneity of the liposarcoma subentities. In the past decade, the rising understanding of the various genetic and molecular aberrations in liposarcoma led to the development of novel alternative therapeutic strategies. One such therapy is the inhibition of the heat shock protein 90 (Hsp90) which is overexpressed in liposarcomas. In this study, we dissect the functional role of a novel potent Hsp90 inhibitor NVP-AUY922 (AUY922) in different cell lines of myxoid (MLS402, MLS1765) and undifferentiated (SW872) liposarcomas. We show that compared with 17-AAG treatment, lower concentrations of AUY922 achieve markedly cytotoxic effects on tumor cell viability. Combination treatment of AUY922 (20 nM) with Doxorubicin (300 nM) yielded a further reduction in cell viability in comparison to Doxorubicin alone. In vivo, we document an inhibition of tumor growth after AUY922 treatment. Further analyses revealed that Hsp90-inhibition induces apoptotic cell death and cell cycle arrest. In addition, we report striking perturbations of subtype-specific pattern in Raf/MEK/ERK and PI3K signaling after AUY922 application. In conclusion, our results provide evidence that Hsp90-inhibition by AUY922 may be a promising alternative therapeutic strategy for myxoid liposarcoma patients.
authors.affiliation: Experimental Tumor Pathology, University Hospital Erlangen of Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 22, 91054 Erlangen, Germany; Institute of Pathology, University Hospital Erlangen of Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Steinmann
authors.affiliation: Department of Biology, American University of Beirut, Beirut, Lebanon.
authors.forename: Hala
authors.initials: H
authors.lastname: Gali-Muhtasib
authors.affiliation: Experimental Tumor Pathology, University Hospital Erlangen of Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 22, 91054 Erlangen, Germany; Institute of Pathology, University Hospital Erlangen of Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Huebner
authors.affiliation: Genomic and Health Laboratory, Faculty of Sciences, R. Hariri Campus, Lebanese University, Hadath, Lebanon.
authors.forename: Racha
authors.initials: R
authors.lastname: Al-Halabi
authors.affiliation: Genomic and Health Laboratory, Faculty of Sciences, R. Hariri Campus, Lebanese University, Hadath, Lebanon.
authors.forename: Raghida
authors.initials: R
authors.lastname: Abou Merhi
authors.affiliation: Sahlgrenska Cancer Center, Department of Pathology, Institute of Biomedicine, University of Gothenburg, 40530 Gothenburg, Sweden.
authors.forename: Pierre
authors.initials: P
authors.lastname: Aman
authors.affiliation: Institute of Pathology, University Hospital Erlangen of Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany.
authors.forename: Abbas
authors.initials: A
authors.lastname: Agaimy
authors.affiliation: Institute of Pathology, University Hospital Erlangen of Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Haller
authors.affiliation: Experimental Tumor Pathology, University Hospital Erlangen of Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 22, 91054 Erlangen, Germany; Institute of Pathology, University Hospital Erlangen of Friedrich-Alexander University Erlangen-Nuremberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany. Electronic address: regine.schneider-stock@uk-erlangen.de.
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D018208:Liposarcoma, Myxoid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D012118:Resorcinols; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt
keywords: Hsp90-inhibition; Liposarcoma; Myxoid; NVP-AUY922