Inhibition of protein arginine methylation alters RNA metabolism and DNA damage response providing a new therapeutic strategy in pancreatic ductal adenocarcinoma

With limited therapeutic options, poor overall 5-year survival rates, and increasing incidence, pancreas cancer is estimated to become the second leading cause of cancer deaths by 2030. Recognizing the need for transformative advances in pancreas cancer management, we developed an in vivo target discovery platform to uncover molecular vulnerabilities in patient-derived pancreatic ductal adenocarcinoma (PDAC) xenografts to identify and rapidly translate novel therapeutic concepts to the clinic. We identified protein arginine methyltransferase 1 (PRMT1) as a dependency in PDAC required for disease maintenance and progression. Extensive genetic and pharmacological studies support PRMT1 as a novel vulnerability, which prompted our design and synthesis of proprietary series of potent, selective PRMT Type I inhibitors (PRMTi) with compelling in vivo activity. While advancing the project in drug discovery, we deployed a comprehensive approach to elucidate the mechanism of action of PRMTi. We characterized the PRMT1 interactome via PRMT1 immunoprecipitation followed by LC/MS and observed that PRMT1 binding partners were significantly enriched in RNA-binding and -processing genes. In addition, because methylation of arginine residues is a common post-translational modification regulating protein function, we identified substrates differentially methylated upon PRMT inhibition. Integrating these results with the PRMT1 interactome confirmed a strong correlation between PRMT1 substrates and complexes that are physically associated and linked to RNA metabolism. Transcriptome assays demonstrated that PRMT inhibition globally impaired RNA metabolism, including but not limited to RNA splicing, transcription termination, and R-loop formation. In addition, PRMTi caused a profound down-regulation of multiple pathways involved in the DNA damage response (DDR) promoting genomic instability. Taken together, these data support PRMT1 as a compelling target in an area of high unmet medical need and inform a mechanism-based translational strategy for future clinical development. Citation Format: Virginia Giuliani, Alessandro Carugo, Meredith Miller, Lionel Sanz, Chiu-Yi Liu, Christopher A Bristow, Erika Suzuki, Caleb A Class, Stella R. Hartono, Guang Gao, Ningping Feng, Jason P Gay, Bhavatarini Vangamudi, Joseph R Marszalek, Jeffrey Kovacs, Maria Emilia Di Francesco, Frederic Chedin, Philip Jones, Giulio Draetta, Timothy Heffernan. Inhibition of protein arginine methylation alters RNA metabolism and DNA damage response providing a new therapeutic strategy in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 277.