Targeting Cyclin-Dependent Kinases in Synovial Sarcoma: Palbociclib as a Potential Treatment for Synovial Sarcoma Patients.
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Authors
Vlenterie, M
Hillebrandt-Roeffen, MHS
Schaars, EWM
Flucke, UE
Fleuren, EDG
Navis, AC
Leenders, WPJ
Versleijen-Jonkers, YMH
van der Graaf, WTA
Hillebrandt-Roeffen, MHS
Schaars, EWM
Flucke, UE
Fleuren, EDG
Navis, AC
Leenders, WPJ
Versleijen-Jonkers, YMH
van der Graaf, WTA
Document Type
Journal Article
Date
2016-09
Date Accepted
Date Available
Abstract
Background In synovial sarcomas alterations in the cyclin D1-CDK4/6-Rb axis have been described. Also, β-catenin, a cyclin D1 regulator, is often overexpressed. Additionally, studies have shown that the t(X;18) translocation influences tumor behavior partly through cyclin D1 activation. We investigated how alterations in the cyclin D1-CDK4/6-Rb axis impact prognosis and studied effects of targeting this axis with the CDK4/6 inhibitor palbociclib.Methods Synovial sarcoma samples (n = 43) were immunohistochemically stained for β-catenin, cyclin D1, p16, p21, p27, Rb, and phospho-Rb. Fluorescent in situ hybridization (FISH) was performed to detect CCND1 amplification or translocation. In 4 synovial sarcoma cell lines sensitivity to palbociclib was investigated using cell viability assays, and effects on the sensitive cell lines were evaluated on protein level and by cell cycle arrest.Results Expression of nuclear phospho-Rb and nuclear β-catenin in the patient samples was associated with poor survival. FISH showed a sporadic translocation of CCND1 in a subset of tumors. An 8-fold CCND1 amplification was found in 1 cell line, but not in the patient samples investigated. Palbociclib effectively inhibited Rb-phosphorylation in 3 cell lines, resulting in an induction of a G1 arrest and proliferation block.Conclusions In this series nuclear phospho-Rb and nuclear β-catenin expression were negative prognostic factors. In vitro data suggest that palbociclib may be a potential treatment for a subset of synovial sarcoma patients. Whether this effect can be enhanced by combination treatment deserves further preclinical investigations.
Citation
Annals of surgical oncology, 2016, 23 (9), pp. 2745 - 2752
Source Title
Publisher
ISSN
1068-9265
eISSN
1534-4681
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Research Team
Clinical and Translational Sarcoma