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HSP90 inhibition bl...
HSP90 inhibition blocks ERBB3 and RET phosphorylation in myxoid/round cell liposarcoma and causes massive cell death in vitro and in vivo
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- Safavi, Setareh (author)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för biomedicin, avdelningen för patologi,Institute of Biomedicine, Department of Pathology,University of Gothenburg,Friedrich-Alexander-Universität Erlangen Nurnberg (FAU)
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- Järnum, Sofia (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för patologi,Sahlgrenska Cancer Center,Institute of Biomedicine, Department of Pathology,University of Gothenburg
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- Vannas, Christoffer (author)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för biomedicin, avdelningen för patologi,Institute of Biomedicine, Department of Pathology,University of Gothenburg
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- Udhane, Sameer (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för patologi,Sahlgrenska Cancer Center,Institute of Biomedicine, Department of Pathology,University of Gothenburg
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- Jonasson, Emma, 1987 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för patologi,Sahlgrenska Cancer Center,Institute of Biomedicine, Department of Pathology,University of Gothenburg
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- Tomic, Tajana Tesan (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för patologi,Sahlgrenska Cancer Center,Institute of Biomedicine, Department of Pathology,University of Gothenburg
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- Grundevik, Pernilla (author)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för biomedicin, avdelningen för patologi,Institute of Biomedicine, Department of Pathology,University of Gothenburg
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- Fagman, Henrik, 1975 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för patologi,Sahlgrenska Cancer Center,Institute of Biomedicine, Department of Pathology,University of Gothenburg
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- Hansson, Magnus (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för patologi,Sahlgrenska Cancer Center,Institute of Biomedicine, Department of Pathology,University of Gothenburg
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- Kalender, Zeynep (author)
- Gothenburg University,Göteborgs universitet,Institutionen för matematiska vetenskaper, matematisk statistik,Department of Mathematical Sciences, Mathematical Statistics,University of Gothenburg,Chalmers tekniska högskola,Chalmers University of Technology
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- Jauhiainen, Alexandra, 1981 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för matematiska vetenskaper, matematisk statistik,Department of Mathematical Sciences, Mathematical Statistics,AstraZeneca AB
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- Dolatabadi, Soheila (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för patologi,Sahlgrenska Cancer Center,Institute of Biomedicine, Department of Pathology,University of Gothenburg
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Stratford, E. W. (author)
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Myklebost, O. (author)
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- Eriksson, Mikael (author)
- Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Stenman, Göran, 1953 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för patologi,Sahlgrenska Cancer Center,Institute of Biomedicine, Department of Pathology,University of Gothenburg
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Stock, R. S. (author)
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- Ståhlberg, Anders, 1975 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för patologi,Sahlgrenska Cancer Center,Institute of Biomedicine, Department of Pathology,University of Gothenburg
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- Åman, Pierre, 1953 (author)
- Gothenburg University,Göteborgs universitet,Sahlgrenska Cancer Center,Institutionen för biomedicin, avdelningen för patologi,Institute of Biomedicine, Department of Pathology,University of Gothenburg
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(creator_code:org_t)
- 2015-11-16
- 2016
- English.
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In: OncoTarget. - : Impact Journals, LLC. - 1949-2553. ; 7:1, s. 433-445
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Abstract
Subject headings
Close
- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Cellbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Cell Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- sarcoma
- receptor tyrosine kinases
- HSP90 inhibitors
- xenografts
- xenografts
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Safavi, Setareh
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Järnum, Sofia
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Vannas, Christof ...
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Udhane, Sameer
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Jonasson, Emma, ...
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Tomic, Tajana Te ...
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show more...
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Grundevik, Perni ...
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Fagman, Henrik, ...
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Hansson, Magnus
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Kalender, Zeynep
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Jauhiainen, Alex ...
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Dolatabadi, Sohe ...
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Stratford, E. W.
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Myklebost, O.
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Eriksson, Mikael
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Stenman, Göran, ...
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Stock, R. S.
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Ståhlberg, Ander ...
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Åman, Pierre, 19 ...
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Cell Biology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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OncoTarget
- By the university
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University of Gothenburg
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Chalmers University of Technology
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Lund University