Targeting Cyclin-Dependent Kinases in Synovial Sarcoma: Palbociclib as a Potential Treatment for Synovial Sarcoma Patients

• Published in: Annals of surgical oncology Vol. 23; no. 9; pp. 2745 - 2752
• Main Authors: Vlenterie, Myrella, Hillebrandt-Roeffen, Melissa H. S., Schaars, Esther W. M., Flucke, Uta E., Fleuren, Emmy D. G., Navis, Anna C., Leenders, William P. J., Versleijen-Jonkers, Yvonne M. H., van der Graaf, Winette T. A.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.09.2016; Springer Nature B.V
• Subjects: Adolescent; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; beta Catenin - metabolism; Bone and Soft Tissue Sarcomas; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclin D1 - genetics; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Female; G1 Phase Cell Cycle Checkpoints - drug effects; Humans; Immunohistochemistry; Male; Medicine; Medicine & Public Health; Oncology; Phosphorylation - drug effects; Piperazines - pharmacology; Piperazines - therapeutic use; Pyridines - pharmacology; Pyridines - therapeutic use; Retinoblastoma Protein - metabolism; Sarcoma, Synovial - drug therapy; Sarcoma, Synovial - genetics; Sarcoma, Synovial - metabolism; Surgery; Surgical Oncology; Survival Rate; Young Adult; Soft Tissue Sarcoma; Synovial Sarcoma; Letrozole; Pazopanib
• ISSN: 1068-9265; 1534-4681
• DOI: 10.1245/s10434-016-5341-x

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.