Epigenetic regulation of p53 represents a targetable dependency in synovial sarcoma

Synovial sarcoma is a deadly malignancy of soft-tissue with a predilection for adolescents and young adults that consistently associates with a t(X;18) chromosomal translocation and expression of the resultant fusion oncoprotein SS18::SSX. Here, the dependency on MDM2 that has been observed in multiple synovial sarcoma cell lines is presented. Very few synovial sarcomas in humans demonstrate TP53 mutation or loss, CDKN2A loss, or MDM2 gains, each common among other sarcoma types. Silencing of homologous Trp53 in a mouse model of SS18::SSX-expression-induced sarcomagenesis leads to a slightly reduced latency to tumorigenesis, but no increase in de-differentiated phenotypes, or nuclear pleiomorphism. Transcriptome analysis revealed minimal change in p53 target gene expression, suggesting that expression of the fusion alone was sufficient to impact these. Treatment of mice with the MDM2-p53-intereaction inhibitor, HDM201, was modestly successful at slowing tumor growth, alone. Combined treatment with HDM201 and the HDAC inhibitor panobinostat, known to be capable of derepressing Cdkn2a expression, synergized to curtail synovial sarcoma development.