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

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. H...

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Bibliographic Details
Published in:Neoplasia (New York, N.Y.) Vol. 61; p. 101138
Main Authors: Ephraums, James, Youkhana, Janet, Raina, Aparna S., Schulstad, Grace, Croft, Kento, Mawson, Amanda, Kokkinos, John, Gonzales-Aloy, Estrella, Ignacio, Rosa Mistica C., McCarroll, Joshua A., Boyer, Cyrille, Goldstein, David, Pajic, Marina, Haghighi, Koroush S., Johns, Amber, Gill, Anthony J., Erkan, Mert, Initiative (APGI), Australian Pancreatic Cancer Genome, Phillips, Phoebe A., Sharbeen, George
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01.03.2025
Elsevier
Subjects:
Animals
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Apoptosis - genetics
Carcinoma, Pancreatic Ductal - drug therapy
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - pathology
Cell Line, Tumor
Cell Proliferation - drug effects
Chemosensitisation
Disease Models, Animal
DNA Damage
DNA Glycosylases - genetics
DNA Glycosylases - metabolism
DNA repair
DNA Repair - genetics
Gene Knockdown Techniques
Humans
Mice
Oxaliplatin
Oxidative stress
Pancreatic cancer
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Phthalazines - pharmacology
Piperazines - pharmacology
RNA, Small Interfering - genetics
Xenograft Model Antitumor Assays
Oxidative stress
Chemosensitisation
DNA repair
Pancreatic cancer
ISSN:1476-5586, 1476-5586
Online Access:Get full text
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Summary: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.
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ISSN:1476-5586
1476-5586
DOI:10.1016/j.neo.2025.101138