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

## TL;DR

This study shows that reducing MYH in pancreatic cancer cells causes DNA damage and makes them more sensitive to certain drugs, offering a new treatment strategy.

## Contribution

The study reveals that MYH inhibition creates a DNA repair vulnerability in pancreatic cancer cells, which can be exploited therapeutically.

## Key findings

- MYH inhibition causes DNA damage and activates checkpoints in pancreatic cancer cells.
- MYH-siRNA delivery using Star 3 nanoparticles increases PDAC cell death in a mouse model.
- MYH knockdown sensitizes PDAC cells to oxaliplatin and olaparib.

## 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.