Synovial sarcoma is a gateway to the role of chromatin remodeling in cancer.
Patients afflicted with synovial sarcoma share the fate of other translocation positive sarcomas; the driver mutation for this cancer is known, yet no means to target the fusion protein SS18-SSX directly exist. Current chemotherapeutic regimens are minimally beneficial, particularly in patients with metastatic disease. SS18-SSX putatively promotes its oncogenic activity through protein-protein interactions that alter genetic programs through chromatin remodeling. This review discusses the functional protein network of SS18-SSX, both wild-type and fusion protein, considers its intrinsically disordered nature, and provides insights into potential therapeutic strategies. A comprehensive overview of the clinical characteristics reveals the need for newly targeted therapeutics based upon oncogenic transformation by the fusion protein SS18-SSX. The wild-type, non-fused proteins SS18 and SSX are presented including their molecular structure and biological function with regard to protein-protein interactions. The interactions of the wild-type proteins inform the oncogenic changes of the fusion protein. The SS18-SSX fusion protein and its protein interactions are described and evaluated for their biological consequences that lead to oncogenesis. This review illustrates the key protein interactions of SS18-SSX that may qualify as primary targets for small molecule-based disruption leading to the development of SS18-SSX-specific drugs. These novel targeted therapeutics may provide a specificity that ultimately improves survival while reducing morbidity of patients with synovial sarcoma.
Department of Oncology, Georgetown University, Research Building, Suite E501, 3970 Reservoir Road, N.W., Washington, DC, 20057, USA.|Department of Pediatric Hematology and Oncology, University Childrens Hospital Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149, Münster, Germany.
Stefan K
SK
Zöllner
Department of Pediatric Hematology and Oncology, University Childrens Hospital Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149, Münster, Germany.
Claudia
C
Rössig
Department of Oncology, Georgetown University, Research Building, Suite E501, 3970 Reservoir Road, N.W., Washington, DC, 20057, USA. jat42@georgetown.edu.|Department of Pediatrics, Georgetown University, Research Building, Suite E501, 3970 Reservoir Road, N.W., Washington, DC, 20057, USA. jat42@georgetown.edu.
Jeffrey A
JA
Toretsky
D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D015195:Drug Design; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D013584:Sarcoma, Synovial / Q000235:genetics*
D015514:Oncogene Proteins, Fusion; C116512:SYT-SSX fusion protein
Fusion protein; Protein interaction; SS18-SSX; SWI/SNF; Synovial sarcoma; Targeted therapy