PRMT1-dependent regulation of RNA metabolism and DNA damage response is a critical dependency in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, which represents a critical area of unmet need for novel therapeutic options. Here we deployed an RNAi-based in vivo functional genomics platform to identify epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this effort, we identified protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validated the role of PRMT1 in maintaining PDAC growth and informed the mechanism-of-action through proteomic and transcriptomic analyses. Mechanistically, we showed that inhibition of asymmetric arginine methylation globally impaired RNA metabolism, including RNA splicing, alternative polyadenylation, and transcription termination, causing a profound down-regulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, these data support PRMT1 as a compelling target in PDAC and inform a mechanism-based translational strategy for future therapeutic development. Identification of PRMT1 as a unique vulnerability in patient-derived PDAC model in vivo using pharmacological and genetic techniques, and characterization of R-loop and transcription landscape in PRMT1 Inhibited PANC1 and PATC53 cells using polyA RNA-seq and sDRIP seq.