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Epigenetic drug screening defines a PRMT5 inhibitor-sensitive pancreatic cancer subtype
Felix Orben1, Katharina Lankes1, Christian Schneeweis1,2
1Medical Clinic and Polyclinic II, Klinikum rechts der Isar and.
Abstract:
Systemic therapies for pancreatic ductal adenocarcinoma (PDAC) remain unsatisfactory. Clinical prognosis is particularly poor for tumor subtypes with activating aberrations in the MYC pathway, creating an urgent need for novel therapeutic targets. To unbiasedly find MYC-associated epigenetic dependencies, we conducted a drug screen in pancreatic cancer cell lines. Here, we found that protein arginine N-methyltransferase 5 (PRMT5) inhibitors triggered an MYC-associated dependency. In human and murine PDACs, a robust connection of MYC and PRMT5 was detected. By the use of gain- and loss-of-function models, we confirmed the increased efficacy of PRMT5 inhibitors in MYC-deregulated PDACs. Although inhibition of PRMT5 was 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 high MYC expression. Experiments in primary patient-derived PDAC models demonstrated the existence of a highly PRMT5 inhibitor-sensitive subtype. Our work suggests developing PRMT5 inhibitor-based therapies for PDAC.
Insights
Protein arginine N-methyltransferase 5 (PRMT5) inhibitors show promise for pancreatic cancer. Targeting PRMT5 is effective in MYC-driven pancreatic ductal adenocarcinoma, revealing a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Systemic therapies for pancreatic ductal adenocarcinoma (PDAC) are limited, with poor prognosis for MYC pathway-activated subtypes.
- Novel therapeutic targets are urgently needed for PDAC, especially for aggressive subtypes.
Purpose of the Study:
- To identify MYC-associated epigenetic dependencies in pancreatic cancer.
- To investigate the therapeutic potential of protein arginine N-methyltransferase 5 (PRMT5) inhibitors in PDAC.
Main Methods:
- Conducted a drug screen in pancreatic cancer cell lines to find MYC-associated dependencies.
- Utilized gain- and loss-of-function models to assess PRMT5 inhibitor efficacy in MYC-deregulated PDAC.
- Examined PRMT5 inhibitor effects on DNA damage, cell cycle arrest, and apoptosis in PDAC cells.
Main Results:
- PRMT5 inhibitors revealed an MYC-associated dependency in pancreatic cancer cells.
- A strong correlation between MYC and PRMT5 was observed in human and murine PDAC.
- PRMT5 inhibition induced DNA damage and G2/M cell cycle arrest, with apoptosis predominantly in high MYC-expressing cells.
- Patient-derived PDAC models identified a PRMT5 inhibitor-sensitive subtype.
Conclusions:
- PRMT5 inhibition demonstrates therapeutic potential in PDAC, particularly in MYC-driven tumors.
- PRMT5 inhibitors represent a promising targeted therapy for a subset of pancreatic ductal adenocarcinoma patients.
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