Effect of PRMT5 inhibitor on gene expression in MTAP null pancreatic cell lines
One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been the dependency on PRMT5 in cancer cells with MTAP deletion. Here we report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor, AMG 193. AMG 193 preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust anti-tumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRASG12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. Finally, AMG 193 is demonstrating promising evidence of clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1 / 2 clinical study. Overall design: To investigate the mechanism of action of the MTA-cooperative PRMT5 inhibitors, we performed bulk RNA-seq on three MTAP-deleted pancreatic cancer cell lines (BxPC3, MIAPACA2 and PSN1) treated with tool compound AM-9747 and DMSO control for 6 days and assessed the global gene expression alterations induced by PRMT5 inhibition.