title: HSP90 inhibition blocks ERBB3 and RET phosphorylation in myxoid/round cell liposarcoma and causes massive cell death in vitro and in vivo.
abstract: Myxoid sarcoma (MLS) is one of the most common types of malignant soft tissue tumors. MLS is characterized by the FUS-DDIT3 or EWSR1-DDIT3 fusion oncogenes that encode abnormal transcription factors. The receptor tyrosine kinase (RTK) encoding RET was previously identified as a putative downstream target gene to FUS-DDIT3 and here we show that cultured MLS cells expressed phosphorylated RET together with its ligand Persephin. Treatment with RET specific kinase inhibitor Vandetanib failed to reduce RET phosphorylation and inhibit cell growth, suggesting that other RTKs may phosphorylate RET. A screening pointed out EGFR and ERBB3 as the strongest expressed phosphorylated RTKs in MLS cells. We show that ERBB3 formed nuclear and cytoplasmic complexes with RET and both RTKs were previously reported to form complexes with EGFR. The formation of RTK hetero complexes could explain the observed Vandetanib resistence in MLS. EGFR and ERBB3 are clients of HSP90 that help complex formation and RTK activation. Treatment of cultured MLS cells with HSP90 inhibitor 17-DMAG, caused loss of RET and ERBB3 phosphorylation and lead to rapid cell death. Treatment of MLS xenograft carrying Nude mice resulted in massive necrosis, rupture of capillaries and hemorrhages in tumor tissues. We conclude that complex formation between RET and other RTKs may cause RTK inhibitor resistance. HSP90 inhibitors can overcome this resistance and are thus promising drugs for treatment of MLS/RCLS.
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Setareh
authors.initials: S
authors.lastname: Safavi
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Järnum
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Vannas
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Sameer
authors.initials: S
authors.lastname: Udhane
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Jonasson
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Tajana Tesan
authors.initials: TT
authors.lastname: Tomic
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Grundevik
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Fagman
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Hansson
authors.affiliation: Mathematical Statistics, Mathematical Sciences, Chalmers University of Technology and the University of Gothenburg, Göteborg, Sweden.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Kalender
authors.affiliation: Mathematical Statistics, Mathematical Sciences, Chalmers University of Technology and the University of Gothenburg, Göteborg, Sweden.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Jauhiainen
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Soheila
authors.initials: S
authors.lastname: Dolatabadi
authors.affiliation: Department of Tumour Biology, The Norwegian Radium Hospital, Oslo University Hospital, Nydalen, Oslo, Norway.
authors.forename: Eva Wessel
authors.initials: EW
authors.lastname: Stratford
authors.affiliation: Department of Tumour Biology, The Norwegian Radium Hospital, Oslo University Hospital, Nydalen, Oslo, Norway.
authors.forename: Ola
authors.initials: O
authors.lastname: Myklebost
authors.affiliation: Department of Oncology, Lund University Hospital, Lund, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Eriksson
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Stenman
authors.affiliation: Experimental Tumor Pathology, Institute of Pathology, University of Erlangen-Nürnberg, Ulmenweg Erlangen, Germany.
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Ståhlberg
authors.affiliation: Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Pierre
authors.initials: P
authors.lastname: Åman
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D018208:Liposarcoma, Myxoid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C512478:EGFR protein, human; C581292:ERBB3 protein, human; D066246:ErbB Receptors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020893:Receptor, ErbB-3
keywords: HSP90 inhibitors; receptor tyrosine kinases; sarcoma; xenografts