PRMT5: An Emerging Target for Pancreatic Adenocarcinoma
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Updated: Oct 16, 2025
Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma
Published on: November 19, 2019
Michael K C Lee1,2,3, Sean M Grimmond2, Grant A McArthur1,3
1Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
Abstract:
The overall survival of pancreatic ductal adenocarcinoma (PDAC) remains poor and its incidence is rising. Targetable mutations in PDAC are rare, thus novel therapeutic approaches are needed. Protein arginine methyltransferase 5 (PRMT5) overexpression is associated with worse survival and inhibition of PRMT5 results in decreased cancer growth across multiple cancers, including PDAC. Emerging evidence also suggests that altered RNA processing is a driver in PDAC tumorigenesis and creates a partial dependency on this process. PRMT5 inhibition induces altered splicing and this vulnerability can be exploited as a novel therapeutic approach. Three possible biological pathways underpinning the action of PRMT5 inhibitors are discussed; c-Myc regulation appears central to its action in the PDAC setting. Whilst homozygous MTAP deletion and symmetrical dimethylation levels are associated with increased sensitivity to PRMT5 inhibition, neither measure robustly predicts its growth inhibitory response. The immunomodulatory effect of PRMT5 inhibitors on the tumour microenvironment will also be discussed, based on emerging evidence that PDAC stroma has a significant bearing on disease behaviour and response to therapy. Lastly, with the above caveats in mind, current knowledge gaps and the implications and rationales for PRMT5 inhibitor development in PDAC will be explored.
Insights
Protein arginine methyltransferase 5 (PRMT5) inhibition shows promise for treating pancreatic ductal adenocarcinoma (PDAC). Targeting PRMT5 exploits altered RNA processing, offering a novel therapeutic strategy for this challenging cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has poor survival rates and rising incidence.
- Targetable mutations are rare in PDAC, necessitating novel therapeutic strategies.
- PRMT5 overexpression correlates with worse survival and inhibits cancer growth.
Purpose of the Study:
- To explore PRMT5 inhibition as a novel therapeutic approach for PDAC.
- To discuss biological pathways, predictive biomarkers, and immunomodulatory effects of PRMT5 inhibitors.
- To identify knowledge gaps and implications for PRMT5 inhibitor development in PDAC.
Main Methods:
- Review of emerging evidence on PRMT5 inhibition in PDAC.
- Discussion of biological pathways, including c-Myc regulation.
- Analysis of potential predictive markers like MTAP deletion and symmetrical dimethylation.
- Exploration of PRMT5 inhibitors' immunomodulatory effects on the tumor microenvironment.
Main Results:
- PRMT5 inhibition impacts RNA processing, specifically altering splicing, presenting a therapeutic vulnerability.
- c-Myc regulation appears central to PRMT5 inhibitor action in PDAC.
- While MTAP deletion and dimethylation levels correlate with sensitivity, they don't robustly predict response.
- PRMT5 inhibitors may modulate the tumor microenvironment, influencing PDAC behavior and therapy response.
Conclusions:
- PRMT5 inhibition represents a promising therapeutic avenue for PDAC by targeting RNA processing vulnerabilities.
- Further research is needed to refine predictive biomarkers and understand the full immunomodulatory potential of PRMT5 inhibitors in PDAC.
- Addressing knowledge gaps is crucial for the rational development of PRMT5 inhibitors for pancreatic cancer treatment.
