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Oncotarget. 2016 Jan 5;7(1):433-45. doi: 10.18632/oncotarget.6336.

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

Author information

1
Sahlgrenska Cancer Center, Institute of Biomedicine, Department of Pathology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
2
Mathematical Statistics, Mathematical Sciences, Chalmers University of Technology and the University of Gothenburg, Göteborg, Sweden.
3
Department of Tumour Biology, The Norwegian Radium Hospital, Oslo University Hospital, Nydalen, Oslo, Norway.
4
Department of Oncology, Lund University Hospital, Lund, Sweden.
5
Experimental Tumor Pathology, Institute of Pathology, University of Erlangen-Nürnberg, Ulmenweg Erlangen, Germany.

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.

KEYWORDS:

HSP90 inhibitors; receptor tyrosine kinases; sarcoma; xenografts

PMID:
26595521
PMCID:
PMC4808009
DOI:
10.18632/oncotarget.6336
[Indexed for MEDLINE]
Free PMC Article

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