Abstract C089: PRMT5 as a novel druggable vulnerability for EWSR1-ATF1-driven clear cell sarcoma

Abstract

Abstract Clear cell sarcoma of soft tissue (CCSST) is a rare and aggressive soft tissue sarcoma. The 5-year survival rate is only 20% for metastatic cases of CCSST. CCSST is insensitive to existing chemotherapies or radiotherapy. New target therapies will have tremendous impact on CCSST patients. The hallmark of CCSST is a chromosome translocation, which generates an oncogene EWSR1-ATF1, where Ewing’s sarcoma gene (EWSR1) is fused with activating transcription factor 1 (ATF1). EWSR1-ATF1 is a constitutively active form of ATF1 and is independent of extracellular cues to drive ATF1-dependent gene transcription. We recently discovered that protein arginine methyltransferase 5 (PRMT5) is involved in EWSR1-ATF1-mediated gene transcription. Genetic silencing of PRMT5 in CCSST cells results in severely inhibited cell growth. We further identified a PRMT5 inhibitor JNJ-64619178 to potently and efficaciously inhibit CCSST cell growth in vitro and in vivo. This becomes clinically very relevant as JNJ-64619178 finished phase I clinical trial (NCT03573310) in advanced solid tumors and non-Hodgkin lymphoma patients and it demonstrated manageable toxicity. Our results presented here provide a strong mechanistic basis for further clinical evaluation of JNJ-64619178 to treat CCSST patients. Citation Format: Bingbing X Li, Larry L David, Lara E Davis, Xiangshu Xiao. PRMT5 as a novel druggable vulnerability for EWSR1-ATF1-driven clear cell sarcoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C089.