Identification of cytotoxic agents disrupting synovial sarcoma oncoprotein interactions by proximity ligation assay.
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.
Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.|Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada.
Aimée N
AN
Laporte
Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada.
Jennifer X
JX
Ji
Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
Limin
L
Ma
Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.|Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, BC, Canada.
Torsten O
TO
Nielsen
Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
Bertha A
BA
Brodin
D000970:Antineoplastic Agents / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056970:Co-Repressor Proteins; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D060066:Protein Interaction Maps; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D013584:Sarcoma, Synovial / Q000188:drug therapy*
D000970:Antineoplastic Agents; D052117:Benzodioxoles; D056970:Co-Repressor Proteins; D056572:Histone Deacetylase Inhibitors; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C587877:SS18-SSX1 fusion protein; C000625796:SXT1596; C499043:TLE1 protein, human
HDAC inhibitors; drug screening; protein-protein association; proximity ligation assay; synovial sarcoma