MYH knockdown in pancreatic cancer cells creates an exploitable DNA repair vulnerability
Neoplasia (United States), cilt.61, 2025 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 61
- Basım Tarihi: 2025
- Doi Numarası: 10.1016/j.neo.2025.101138
- Dergi Adı: Neoplasia (United States)
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, MEDLINE, Directory of Open Access Journals
- Anahtar Kelimeler: Chemosensitisation, DNA repair, Oxidative stress, Pancreatic cancer
- Acıbadem Mehmet Ali Aydınlar Üniversitesi Adresli: Evet
Özet
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.