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Identification of PRMT5 as a therapeutic target in cholangiocarcinoma
Jasmin Elurbide1,2, Leticia Colyn1, Maria U Latasa3
1Hepatology Laboratory, CIMA-University of Navarra, Pamplona, Spain.
Background:
Cholangiocarcinoma (CCA) is a very difficult-to-treat cancer. Chemotherapies are little effective and response to immune checkpoint inhibitors is limited. Therefore, new therapeutic strategies need to be identified.
Objective:
We characterised the enzyme protein arginine-methyltransferase 5 (PRMT5) as a novel therapeutic target in CCA.
Design:
We evaluated the expression of PRMT5, its functional partner MEP50 and methylthioadenosine phosphorylase (MTAP)-an enzyme that modulates the sensitivity of PRMT5 to pharmacological inhibitors-in human CCA tissues. PRMT5-targeting drugs, currently tested in clinical trials for other malignancies, were assessed in human CCA cell lines and organoids, as well as in two immunocompetent CCA mouse models. Transcriptomic, proteomic and functional analyses were performed to explore the underlying antitumoural mechanisms.
Results:
PRMT5 and MEP50 proteins were correlatively overexpressed in most CCA tissues. MTAP was absent in 25% of intrahepatic CCA. PRMT5-targeting drugs markedly inhibited CCA cell proliferation, synergising with cisplatin and gemcitabine and hindered the growth of cholangiocarcinoma organoids. PRMT5 inhibition blunted the expression of oncogenic genes involved in chromatin remodelling and DNA repair, consistently inducing the formation of RNA loops and promoting DNA damage. Treatment with PRMT5-targeting drugs significantly restrained the growth of experimental CCA without adverse effects and concomitantly induced the recruitment of CD4 and CD8 T cells to shrinking tumourous lesions.
Conclusion:
PRMT5 and MEP50 are frequently upregulated in human CCA, and PRMT5-targeting drugs have significant antitumoural efficacy in clinically relevant CCA models. Our findings support the evaluation of PRMT5 inhibitors in clinical trials, including their combination with cytotoxic and immune therapies.
Insights
Targeting protein arginine-methyltransferase 5 (PRMT5) shows promise for treating cholangiocarcinoma (CCA). PRMT5 inhibitors effectively reduced CCA growth in models, suggesting a new therapeutic strategy for this difficult-to-treat cancer.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Cholangiocarcinoma (CCA) is a challenging cancer with limited treatment options.
- Current chemotherapies and immune checkpoint inhibitors show minimal efficacy in CCA.
- Novel therapeutic targets are urgently needed for effective CCA treatment.
Purpose of the Study:
- To investigate protein arginine-methyltransferase 5 (PRMT5) as a potential therapeutic target in CCA.
- To evaluate the efficacy of PRMT5-targeting drugs in preclinical CCA models.
- To elucidate the antitumoural mechanisms of PRMT5 inhibition in CCA.
Main Methods:
- Assessed PRMT5, MEP50, and methylthioadenosine phosphorylase (MTAP) expression in human CCA tissues.
- Tested PRMT5-targeting drugs in human CCA cell lines, organoids, and immunocompetent mouse models.
- Performed transcriptomic, proteomic, and functional analyses to understand mechanisms.
Main Results:
- PRMT5 and MEP50 were overexpressed in most CCA tissues; MTAP was absent in 25% of intrahepatic CCAs.
- PRMT5 inhibitors significantly inhibited CCA cell proliferation and organoid growth, synergizing with cisplatin and gemcitabine.
- PRMT5 inhibition reduced oncogenic gene expression, induced RNA loops, promoted DNA damage, and recruited T cells.
Conclusions:
- PRMT5 and MEP50 are frequently upregulated in human CCA.
- PRMT5-targeting drugs demonstrate significant antitumoural efficacy in preclinical CCA models.
- PRMT5 inhibitors warrant clinical evaluation, potentially in combination with cytotoxic and immune therapies.
