MYH knockdown in pancreatic cancer cells creates an exploitable DNA repair vulnerability

  • Neoplasia. 2025 Mar:61:101138. doi: 10.1016/j.neo.2025.101138.
James Ephraums  1 ,  Janet Youkhana  1 ,  Aparna S Raina  1 ,  Grace Schulstad  1 ,  Kento Croft  1 ,  Amanda Mawson  2 ,  John Kokkinos  3 ,  Estrella Gonzales-Aloy  4 ,  Rosa Mistica C Ignacio  4 ,  Joshua A McCarroll  5 ,  Cyrille Boyer  6 ,  David Goldstein  7 ,  Marina Pajic  8 ,  Koroush S Haghighi  9 ,  Amber Johns  10 ,  Anthony J Gill  11 ,  Mert Erkan  12 ,  Australian Pancreatic Cancer Genome Initiative Apgi  13 ,  Phoebe A Phillips  14 ,  George Sharbeen  15
Affiliations
  • 1. Pancreatic Cancer Translational Research Group, School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney; NSW 2052, Australia.
  • 2. Pancreatic Cancer Translational Research Group, School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney; NSW 2052, Australia; Garvan Institute of Medical Research; NSW 2010, Australia.
  • 3. Pancreatic Cancer Translational Research Group, School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney; NSW 2052, Australia; Australian Centre for Nanomedicine (ACN), UNSW Sydney, Australia.
  • 4. Pancreatic Cancer Translational Research Group, School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney; NSW 2052, Australia; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney; NSW 2052, Australia.
  • 5. Australian Centre for Nanomedicine (ACN), UNSW Sydney, Australia; Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney; NSW 2052, Australia.
  • 6. Australian Centre for Nanomedicine (ACN), UNSW Sydney, Australia; Cluster for Advanced Macromolecular Design, School of Chemical Engineering, UNSW Sydney; NSW 2052, Australia.
  • 7. Pancreatic Cancer Translational Research Group, School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney; NSW 2052, Australia; Prince of Wales Hospital, School of Clinical Medicine, Randwick Clinical Campus, UNSW Sydney; NSW 2052, Australia.
  • 8. The Kinghorn Cancer Centre, Garvan Institute of Medical Research; NSW 2010, Australia; School of Clinical Medicine, St Vincent's Healthcare Campus, UNSW Sydney; NSW 2052, Australia.
  • 9. Prince of Wales Hospital, School of Clinical Medicine, Randwick Clinical Campus, UNSW Sydney; NSW 2052, Australia.
  • 10. Garvan Institute of Medical Research; NSW 2010, Australia.
  • 11. The Kinghorn Cancer Centre, Garvan Institute of Medical Research; NSW 2010, Australia; Australian Pancreatic Cancer Genome Initiative (APGI), Garvan Institute of Medical Research; NSW 2010, Australia; Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital; NSW 2065, Australia; University of Sydney; Sydney, NSW 2006, Australia.
  • 12. Mehmet Ali Aydinlar Acibadem University, Atakent University Hospital; Istanbul 34303, Turkey.
  • 13. Australian Pancreatic Cancer Genome Initiative (APGI), Garvan Institute of Medical Research; NSW 2010, Australia.
  • 14. Pancreatic Cancer Translational Research Group, School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney; NSW 2052, Australia; Australian Centre for Nanomedicine (ACN), UNSW Sydney, Australia. Electronic address: [email protected].
  • 15. Pancreatic Cancer Translational Research Group, School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney; NSW 2052, Australia. Electronic address: [email protected].
PMID: 39938155 DOI: 10.1016/j.neo.2025.101138
Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate of just 13 %. Conventional therapies fail due to acquired chemoresistance. We previously identified MutY-Homolog (MYH), a protein that repairs oxidative DNA damage, as a therapeutic target that induces Apoptosis in PDAC cells. However, we did not understand the mechanism driving these anti-PDAC effects, nor did we have a means to therapeutically inhibit MYH. In this study, we demonstrated that MYH inhibition induces DNA damage and checkpoint activation in PDAC cells. Using a clinically-relevant PDAC mouse model, we showed that therapeutic MYH-siRNA delivery using Star 3 nanoparticles increased intratumoural PDAC cell death, but did not inhibit tumour growth. Finally, we showed that MYH knockdown in PDAC cells sensitised them to the anti-proliferative and anti-clonogenic effects of oxaliplatin and olaparib. Our findings identify a potential novel therapeutic approach for PDAC that induces a therapeutically exploitable DNA repair vulnerability.

Keywords
Chemosensitisation; DNA repair; Oxidative stress; Pancreatic cancer.
Products