Abstract 1098: Identification of SUMO2 as a novel therapeutic target for synovial sarcoma
Authors: Iyer Rema , Bala Pramod Akula , Murad Rabi , Deshpande Aniruddha J. 
Published: March 2024

Synovial Sarcoma (SySa) is a rare soft tissue sarcoma that accounts for 5 - 10% of all soft tissue sarcomas. It disproportionately affects children, adolescents and young adults with tumors emerging in muscles, tendons, nerve tissue and joints. Current treatment involves radiation and radical surgery including limb amputation with overall survival around 50% highlighting the urgent need to develop targeted therapies for these patients. In this study, we hypothesized that the fusion SS18-SSX protein found in SySa transcriptionally rewires the tumor cells creating a dependence on specific genes that if uncovered can be exploited therapeutically. To study genes that are selectively essential to SySa, we analyzed the dependency maps (DepMap) whole genome RNAi and CRISPR screening datasets consisting of ~1750 human cancer cell lines including 9 SySa cell lines. We identified 368 target genes that specifically impact the proliferation of SySa when compared to other tumor cell lines. To interrogate these genes systematically, we designed pooled CRISPR libraries and conducted in vitro as well as in vivo screens in SySa cell line HS-SY-II. Our screens revealed that Small Ubiquitin like-modifier 2 (SUMO2) was one of the most significant dependencies in both the in vitro as well as in vivo screens. We tested the SUMO2 inhibitor, TAK-981, a clinical stage small molecule inhibitor specific for E1 SUMO-activating enzyme (SAE), against a panel of SySa cell lines with HS-SY-II and SYO1 showing an EC50 in the low nanomolar range. Furthermore, TAK-981 treatment potently induced apoptosis and reduced the proportion of cycling cells in both HS-SY-II as well as SYO1 cell lines. Strikingly, transcriptomic studies on HS-SY-II and SYO1 cell lines showed that TAK-981 treatment substantially altered the oncogenic signatures of SySa. This was evident both in the HS-SY-II cell line expressing the SS18-SSX1 fusion as well as the SYO1 cell line expressing the SS18-SSX2 fusion protein. These data strongly indicate that SUMO2 is critical for the transcriptional activity of the different SS18-SSX chimeric oncoproteins. In addition, TAK-981 treatment showed a highly significant downregulation of genes associated with cell cycle progression as well as a modulation of genes of the BAF and PRC1/PRC2 complexes that have been implicated in SySa pathogenesis. Taken together, we developed an integrated computational and experimental screening approach to prioritize and validate selective dependencies in synovial sarcoma. Our studies identify SUMO2 as a novel, selective vulnerability in this cancer and since SUMO2 inhibitors are currently in Phase 1/2 clinical trials for other malignancies, our findings present a novel potential avenue for targeted treatment of synovial sarcoma.

Citation Format: Rema Iyer, Pramod Akula Bala, Rabi Murad, Aniruddha J. Deshpande. Identification of SUMO2 as a novel therapeutic target for synovial sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1098.