Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development.Statement of significancePDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage
Our studies demonstrated that asymmetric di-methylarginine (ADMA) is required for faithful RNA processing as well as for the expression of multiple genes and pathways required for supporting PDAC maintenance and genome stability, including cell cycle and DNA damage repair (DDR) networks
In this study, we identified protein arginine methyltransferase 1 (PRMT1) as a novel vulnerability in PDAC using our in vivo PILOT screening platform to identify genetic drivers of tumorigenesis
Summary
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors. We employed our in vivo target discovery platform, PILOT (Patientbased In vivo Lethality to Optimize Treatment),[5] to systematically uncover epigenetic dependencies in a panel of patient-derived xenograft (PDX) models of PDAC Through this unbiased approach, we identified protein arginine methyltransferase 1 (PRMT1) as a top-scoring hit and a novel genetic vulnerability in PDAC. We confirmed the requirement of PRMT1 to maintain in vivo growth of PDAC PDXs, suggesting a mechanism-based translational hypothesis for the clinical development of PRMT1 inhibitors
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