Identification of cytotoxic agents disrupting synovial sarcoma oncoprotein interactions by proximity ligation assay
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Aimée N. Laporte1,2, Jennifer X. Ji2, Limin Ma3, Torsten O. Nielsen1,2, Bertha A. Brodin3
1Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
2Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada
3Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
Torsten O. Nielsen, email: [email protected]
Keywords: synovial sarcoma, proximity ligation assay, drug screening, HDAC inhibitors, protein-protein association
Received: September 09, 2015 Accepted: April 02, 2016 Published: April 21, 2016
Conventional cytotoxic therapies for synovial sarcoma provide limited benefit. Drugs specifically targeting the product of its driver translocation are currently unavailable, in part because the SS18-SSX oncoprotein functions via aberrant interactions within multiprotein complexes. Proximity ligation assay is a recently-developed method that assesses protein-protein interactions in situ. Here we report use of the proximity ligation assay to confirm the oncogenic association of SS18-SSX with its co-factor TLE1 in multiple human synovial sarcoma cell lines and in surgically-excised human tumor tissue. SS18-SSX/TLE1 interactions are disrupted by class I HDAC inhibitors and novel small molecule inhibitors. This assay can be applied in a high-throughput format for drug discovery in fusion-oncoprotein associated cancers where key effector partners are known.
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