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. 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.
Authors
- Cyrille Andre Boyer (ORCID: https://orcid.org/0000-0002-4564-4702)
- Amanda Mawson (ORCID: https://orcid.org/0000-0002-2534-6492)
- David Goldstein (ORCID: https://orcid.org/0000-0001-6142-3291)
- Estrella Gonzales‐Aloy (ORCID: https://orcid.org/0000-0003-4323-2904)
- Phoebe A. Phillips (ORCID: https://orcid.org/0000-0002-4481-8782)
- Koroush S. Haghighi (ORCID: https://orcid.org/0000-0002-3834-463X)
- Mert Erkan (ORCID: https://orcid.org/0000-0002-2753-0234)
- Aparna Raina
- Grace Schulstad
- Anthony James Gill (ORCID: https://orcid.org/0000-0002-9447-1967)
- Amber L. Johns (ORCID: https://orcid.org/0000-0002-1948-6683)
- K.M. Croft
- Rosa Mistica C. Ignacio (ORCID: https://orcid.org/0000-0002-5343-4190)
- Janet Youkhana
- George Sharbeen (ORCID: https://orcid.org/0000-0002-6373-1930)
- Marina Pajic (ORCID: https://orcid.org/0000-0002-3871-3829)
- John Kokkinos (ORCID: https://orcid.org/0000-0002-9819-2404)
- Australian Pancreatic Cancer Genome Initiative Apgi
- Joshua A. McCarroll (ORCID: https://orcid.org/0000-0001-8807-3623)
- James Ephraums
Institutions
- Garvan Institute of Medical Research (AU)
- Cancer Institute of New South Wales (AU)
- UNSW Sydney (AU)
- Cancer Australia (AU)
- Prince of Wales Hospital (AU)
- Children's Cancer Institute Australia (AU)
- Kent Hastanesi (TR)
- The Kinghorn Cancer Centre (AU)
Publication Details
- Journal
- Neoplasia
- Published
- 2025-02-11
- DOI
- https://doi.org/10.1016/j.neo.2025.101138
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Analytical Center for the Government of the Russian Federation
- Cancer Australia
- Cancer Institute NSW
- University of New South Wales
- PanKind, The Australian Pancreatic Cancer Foundation
- National Health and Medical Research Council