{"doi":"10.1101/2022.03.23.485409","title":"PRMT5 as a Novel Druggable Vulnerability for EWSR1-ATF1-driven Clear Cell Sarcoma","abstract":"Abstract Clear cell sarcoma of soft tissue (CCSST) is an ultra-rare sarcoma with poor prognosis presently with no cure. It is characterized by a balanced t(12;22) (q13;q12) chromosomal translocation, resulting in a fusion of the Ewing’s sarcoma gene EWSR1 with activating transcription factor 1 ( ATF1 ) to give an oncogene EWSR1-ATF1 . Unlike normal ATF1, whose transcription activity is dependent on phosphorylation, EWSR1-ATF1 is constitutively active to drive ATF1-dependent gene transcription to cause tumorigenesis. No EWSR1-ATF1-targeted therapies have been identified due to the challenges in targeting intracellular transcription factors. To identify potential druggable targets for CCSST, we show that protein arginine methyltransferase 5 (PRMT5) is a novel enzyme in enhancing EWSR1-ATF1-mediated gene transcription to sustain CCSST cell proliferation. Genetic silencing of PRMT5 in CCSST cells resulted in severely impaired cell proliferation and EWSR1-ATF1-driven transcription. Furthermore, the clinical-stage PRMT5 inhibitor JNJ-64619178 potently and efficaciously inhibited CCSST cell growth in vitro and in vivo . These results provide new insights into PRMT5 as a transcription regulator and warrant JNJ-64619178 for further clinical development to treat CCSST patients.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":306666,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9549,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":141412,"name":"Larry L. David","orcid":null,"position":1,"is_corresponding":false},{"id":244421,"name":"Lara E. Davis","orcid":"0000-0002-6480-1611","position":2,"is_corresponding":false},{"id":255386,"name":"Xiangshu Xiao","orcid":"0000-0001-9520-1371","position":3,"is_corresponding":false},{"id":729131,"name":"Bingbing X. Li","orcid":null,"position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T00:32:52.703737Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}