HSP90 inhibition blocks ERBB3 and RET phosphorylation in myxoid/round cell liposarcoma and causes massive cell death in vitro and in vivo
Journal article, 2016

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.



HSP90 inhibitors

receptor tyrosine kinases


Setareh Safavi

University of Gothenburg

Sofia Järnum

University of Gothenburg

Christoffer Vannas

University of Gothenburg

Sameer Udhane

University of Gothenburg

Emma Jonasson

University of Gothenburg

Tajana Tesan Tomic

University of Gothenburg

Pernilla Grundevik

University of Gothenburg

Henrik Fagman

University of Gothenburg

Magnus Hansson

University of Gothenburg

Zeynep Kalender

University of Gothenburg

Student at Chalmers

Alexandra Jauhiainen

AstraZeneca AB

Soheila Dolatabadi

University of Gothenburg

E. W. Stratford

Rikshospitalet-Radiumhospitalet HF

O. Myklebost

Rikshospitalet-Radiumhospitalet HF

M. Eriksson

Skåne University Hospital

Göran Stenman

University of Gothenburg

R. S. Stock

University of Erlangen-Nuremberg (FAU)

Anders Ståhlberg

University of Gothenburg

Pierre Åman

University of Gothenburg


19492553 (eISSN)

Vol. 7 1 433-445

Subject Categories

Cell Biology

Cancer and Oncology



More information

Latest update