PRMT5 as a Novel Druggable Vulnerability for EWSR1-ATF1-driven Clear Cell Sarcoma

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.