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Hsp90 inhibition by AUY922 as an effective treatment strategy against myxoid liposarcoma

Journal article
Authors S. Steinmann
H. Gali-Muhtasib
K. Huebner
R. Al-Halabi
R. Abou Merhi
Pierre Åman
A. Agaimy
F. Haller
R. Schneider-Stock
Published in Cancer Letters
Volume 367
Issue 2
Pages 147-156
ISSN 0304-3835
Publication year 2015
Published at Institute of Biomedicine, Department of Pathology
Sahlgrenska Cancer Center
Pages 147-156
Language en
Links dx.doi.org/10.1016/j.canlet.2015.07...
Keywords Liposarcoma, Hsp90-inhibition, NVP-AUY922, Myxoid, GASTROINTESTINAL STROMAL TUMOR, CANCER CELLS, PATHWAY, APOPTOSIS, KINASE, GROWTH, EXTREMITY, SURVIVAL, IMATINIB, Oncology
Subject categories Cancer and Oncology

Abstract

Liposarcoma is one of the most common soft tissue sarcomas in adults. Recognized histological subtypes include well differentiated/dedifferentiated liposarcoma (WD/DDLS), myxoid liposarcoma (MLS) and pleomorphic liposarcoma. Currently, there are no proper subtype-specific treatments due to the genetic, histological and clinical heterogeneity of the liposarcoma subentities. In the past decade, the rising understanding of the various genetic and molecular aberrations in liposarcoma led to the development of novel alternative therapeutic strategies. One such therapy is the inhibition of the heat shock protein 90 (Hsp90) which is overexpressed in liposarcomas. In this study, we dissect the functional role of a novel potent Hsp90 inhibitor NVP-AUY922 (AUY922) in different cell lines of myxoid (ML5402, MLS1765) and undifferentiated (SW872) liposarcomas. We show that compared with 17-AAG treatment, lower concentrations of AUY922 achieve markedly cytotoxic effects on tumor cell viability. Combination treatment of AUY922 (20 nM) with Doxorubicin (300 nM) yielded a further reduction in cell viability in comparison to Doxorubicin alone. In vivo, we document an inhibition of tumor growth after AUY922 treatment. Further analyses revealed that Hsp90-inhibition induces apoptotic cell death and cell cycle arrest. In addition, we report striking perturbations of subtype-specific pattern in Raf/MEK/ERK and PI3K signaling after AUY922 application. In conclusion, our results provide evidence that Hsp90-inhibition by AUY922 may be a promising alternative therapeutic strategy for myxoid liposarcoma patients. (C) 2015 Published by Elsevier Ireland Ltd.

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