Identification of PRMT5 as a therapeutic target in cholangiocarcinoma

  • Gut. 2024 Sep 11:gutjnl-2024-332998. doi: 10.1136/gutjnl-2024-332998.
Jasmin Elurbide  1  2 ,  Leticia Colyn  1 ,  Maria U Latasa  3 ,  Iker Uriarte  1  2 ,  Stefano Mariani  1  4 ,  Amaya Lopez-Pascual  1  5 ,  Emiliana Valbuena  1 ,  Borja Castello-Uribe  1 ,  Robert Arnes-Benito  6 ,  Elena Adan-Villaescusa  7 ,  Luz A Martinez-Perez  1  8 ,  Mikel Azkargorta  9 ,  Felix Elortza  10 ,  Hanghang Wu  11 ,  Marcin Krawczyk  12  13 ,  Kai Markus Schneider  14 ,  Bruno Sangro  15 ,  Luca Aldrighetti  16 ,  Francesca Ratti  17 ,  Andrea Casadei Gardini  18 ,  Jose J G Marin  2  19 ,  Irene Amat  20  21 ,  Jesus M Urman  21  22 ,  Maria Arechederra  23 ,  Maria Luz Martinez-Chantar  2  24 ,  Christian Trautwein  25 ,  Meritxell Huch  6 ,  Francisco Javier Cubero  2  26 ,  Carmen Berasain  27 ,  Maite G Fernandez-Barrena  28 ,  Matias A Avila  29
Affiliations
  • 1. Hepatology Laboratory, CIMA-University of Navarra, Pamplona, Spain.
  • 2. CIBEREHD, Madrid, Spain.
  • 3. Hepatology and Gene Therapy, Cima. University of Navarra, Pamplona, Spain.
  • 4. Oncology, University Hospital of Cagliari Department of Medicine, Cagliari, Italy.
  • 5. IdiSNA, Pamplona, Spain.
  • 6. Max-Plank Institute for Molecular Cell Biology and Genetics, Dresden, Germany.
  • 7. Hepatology, CIMA-University of Navarra, Pamplona, Spain.
  • 8. Universidad de Guadalajara Centro Universitario de Ciencias de la Salud, Guadalajara, Mexico.
  • 9. Proteomics Platform, Bizkaia Science and Technology Park, Derio, Spain.
  • 10. Proteomics Platform, CIC bioGUNE, ProteoRed-ISCIII, Bizkaia Science and Technology Park, CIC bioGUNE, Bizkaia, Spain.
  • 11. Immunology, Ophthalmology and ENT, Complutense University of Madrid Faculty of Medicine, Madrid, Spain.
  • 12. Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
  • 13. Laboratory of Metabolic Liver Diseases, Medical University of Warsaw, Warszawa, Poland.
  • 14. Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
  • 15. Liver Unit, Dept. of Internal Medicine, Clinica Universitaria de Navarra, Pamplona, Spain.
  • 16. IRCCS Ospedale San Raffaele, Milano, Italy.
  • 17. Hepatobiliary surgery division, San Raffaele Hospital, Milano, Italy.
  • 18. San Raffaele del Monte Tabor Foundation, Milano, Italy.
  • 19. HEVEFARM, Physiology and Pharmacology, IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain.
  • 20. Department of Pathology, Navarra University Hospital Complex, Pamplona, Spain.
  • 21. Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain.
  • 22. Department of Gastroenterology and Hepatology, Navarra University Hospital Complex, Pamplona, Spain.
  • 23. Centro de Investigacion Medica Aplicada, Pamplona, Spain.
  • 24. Liver Disease Lab, BRTA CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), CICbioGUNE, Derio, Spain.
  • 25. IfADo, Dortmund, Germany.
  • 26. Immunology, Ophthalmology and ENT. Health Research Institute Gregorio Marañón (IiSGM), Complutense University of Madrid Faculty of Medicine, Madrid, Spain.
  • 27. Division of Hepatology and Gene Therapy, CIMA University of Navarra, Pamplona, Spain.
  • 28. Hepatology, FIMA, Pamplona, Spain.
  • 29. Hepatology, CIMA-University of Navarra, Pamplona, Spain [email protected].
PMID: 39266051 DOI: 10.1136/gutjnl-2024-332998
Abstract

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.

Keywords
CHOLANGIOCARCINOMA; MOLECULAR MECHANISMS; PHARMACOTHERAPY.
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