Oncotarget

Research Papers:

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

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, Eva Wessel Stratford, Ola Myklebost, Mikael Eriksson, Göran Stenman, Regine Schneider Stock, Anders Ståhlberg, Pierre Åman _

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Oncotarget. 2016; 7:433-445. https://doi.org/10.18632/oncotarget.6336

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Abstract

Setareh Safavi1, Sofia Järnum1, Christoffer Vannas1, Sameer Udhane1, Emma Jonasson1, Tajana Tesan Tomic1, Pernilla Grundevik1, Henrik Fagman1, Magnus Hansson1, Zeynep Kalender2, Alexandra Jauhiainen2, Soheila Dolatabadi1, Eva Wessel Stratford3, Ola Myklebost3, Mikael Eriksson4, Göran Stenman1, Regine Schneider Stock5, Anders Ståhlberg1, Pierre Åman1

1Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

2Mathematical Statistics, Mathematical Sciences, Chalmers University of Technology and the University of Gothenburg, Göteborg, Sweden

3Department of Tumour Biology, The Norwegian Radium Hospital, Oslo University Hospital, Nydalen, Oslo, Norway

4Department of Oncology, Lund University Hospital, Lund, Sweden

5Experimental Tumor Pathology, Institute of Pathology, University of Erlangen-Nürnberg, Ulmenweg Erlangen, Germany

Correspondence to:

Pierre Åman, e-mail: pierre.aman@gu.se

Keywords: sarcoma, receptor tyrosine kinases, HSP90 inhibitors, xenografts

Received: April 27, 2015     Accepted: October 30, 2015     Published: November 16, 2015

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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