MYH knockdown in pancreatic cancer cells creates an exploitable DNA repair vulnerability
Neoplasia (United States), vol.61, 2025 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 61
- Publication Date: 2025
- Doi Number: 10.1016/j.neo.2025.101138
- Journal Name: Neoplasia (United States)
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, MEDLINE, Directory of Open Access Journals
- Keywords: Chemosensitisation, DNA repair, Oxidative stress, Pancreatic cancer
- Acibadem Mehmet Ali Aydinlar University Affiliated: Yes
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.