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HSP90 inhibition blocks ERBB3 and RET phosphorylation in myxoid/round cell liposarcoma and causes massive cell death in vitro and in vivo

Journal article
Authors Setareh Safavi
Sofia Järnum
Christoffer Vannas
Sameer Udhane
Emma Jonasson
Tajana Tesan Tomic
Pernilla Grundevik
Henrik Fagman
Magnus Hansson
Zeynep Kalender
Alexandra Jauhiainen
Soheila Dolatabadi
E. W. Stratford
O. Myklebost
M. Eriksson
Göran Stenman
R. S. Stock
Anders Ståhlberg
Pierre Åman
Published in OncoTarget
Volume 7
Issue 1
Pages 433-445
ISSN 1949-2553
Publication year 2016
Published at Institute of Biomedicine, Department of Pathology
Sahlgrenska Cancer Center
Department of Mathematical Sciences, Mathematical Statistics
Pages 433-445
Language en
Links dx.doi.org/10.18632/oncotarget.6336
https://gup.ub.gu.se/file/205106
Keywords sarcoma, receptor tyrosine kinases, HSP90 inhibitors, xenografts
Subject categories Cell Biology, Cancer and Oncology

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.

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