Epigenetic drug screening defines a PRMT5 inhibitor–sensitive pancreatic cancer subtype

• DOI: 10.1172/jci.insight.151353
• Publication Date: 2022-04-19T16:08:30Z
• Authors: Felix Orben; Katharina Lankes; Christian Schneeweis; Zonera Hassan; Hannah Jakubowsky; Lukas Krauß; Fabio Boniolo; Carolin Schneider; Arlett Schäfer; Janine Murr; Christoph Schlag; Bo Kong; Rupert Öllinger; Chengdong Wang; Georg Beyer; Ujjwal M. Mahajan; Yonggan Xue; Julia Mayerle; Roland M. Schmid; Bernhard Kuster; Roland Rad; Christian J. Braun; Matthias Wirth; Maximilian Reichert; Dieter Saur; Günter Schneider
• Keywords: 0301 basic medicine; Cell biology; Protein-Arginine N-Methyltransferases; R; Drug Evaluation, Preclinical; ddc:; Epigenesis, Genetic; 3. Good health; Pancreatic Neoplasms; Proto-Oncogene Proteins c-myc; Mice; 03 medical and health sciences; Oncology; Cell Line, Tumor; Medicine; Animals; Humans; Enzyme Inhibitors; Early Detection of Cancer; Research Article; Carcinoma, Pancreatic Ductal

Systemic therapies for pancreatic ductal adenocarcinoma (PDAC) remain unsatisfactory. Clinical prognosis is particularly poor tumor subtypes with activating aberrations in the MYC pathway, creating an urgent need novel therapeutic targets. To unbiasedly find MYC-associated epigenetic dependencies, we conducted a drug screen cancer cell lines. Here, found that protein arginine N-methyltransferase 5 (PRMT5) inhibitors triggered dependency. In human and murine PDACs, robust connection of PRMT5 was detected. By use gain- loss-of-function models, confirmed increased efficacy MYC-deregulated PDACs. Although inhibition inducing DNA damage arresting PDAC cells G2/M phase cycle, apoptotic death executed predominantly high expression. Experiments primary patient-derived models demonstrated existence highly inhibitor-sensitive subtype. Our work suggests developing inhibitor-based PDAC.