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

Ephraums J., Youkhana J., Raina A. S., Schulstad G., Croft K., Mawson A., ...Daha Fazla

Neoplasia (United States), cilt.61, 2025 (SCI-Expanded, Scopus) identifier identifier identifier

  • 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.