Part1: Epigenetic Drug Screening Defines a PRMT5 Inhibitor Sensitive Pancreatic Cancer Subtype; Part2: Indirect targeting of MYC sensitizes pancreatic cancer cellsto mechanistic target of rapamycin (mTOR) inhibition

Part1: To unbiasedly find novel MYC-associated epigenetic dependencies, we conducted a drug screen in pancreatic cancer cell lines. Here, we found protein arginine N-methyltransferase 5 (PRMT5) inhibitors to trigger a MYC-associated dependency. In human and murine PDACs, a robust connection of MYC and PRMT5 was detected. Using mechanistic gain-of-function models we confirm the increased efficacy of PRMT5 inhibitors in MYC deregulated PDACs. Although inhibition of PRMT5 is inducing DNA-damage and arresting PDAC cells in the G2/M-phase of the cell cycle, apoptotic cell death was executed predominantly in cells with deregulated expression of MYC. Experiments in primary patient-derived PDAC organoids demonstrated the existence of a highly PRMT5 inhibitor sensitive subtype. Our work suggests to develop PRMT5 inhibitors-based therapies for PDAC. PMID 35439169 Samples: SAMEA13318665-SAMEA13318688 Part2: We investigated the characteristics of MTOR inhibitor (MTORi) resistant human and murine PDACs. We observed that MTORi resistant PDAC are characterized by activity of the MYC network. To test the contribution of MYC towards MTOR inhibitor resistance, we indirectly targeted MYC by bromodomain and extra-terminal motif (BET) protein inhibitors (BETi). We show that a subset of human and murine PDAC cells as well as primary patient-derived organoids revealed a synergistic response towards a combination therapy of MTORi with BETi. Mechanistically, this combination converges on MYC expression to impair cell cycle progression. Therefore, our work points to a novel combination therapy in a PDAC subtype characterized by MYC and MTOR activity. PMID 35253411 Samples: SAMEA14387666-SAMEA14387667; SAMEA14387669-SAMEA14387698