2. Academic Validation
  3. MYH knockdown in pancreatic cancer cells creates an exploitable DNA repair vulnerability

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

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: p.phillips@unsw.edu.au.
  • 15 Pancreatic Cancer Translational Research Group, School of Biomedical Sciences, Lowy Cancer Research Centre, UNSW Sydney; NSW 2052, Australia. Electronic address: g.sharbeen@unsw.edu.au.
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.

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