Abstract 883: PRDX4 as a novel target for pancreatic cancer

Pancreatic cancer (PCa) is a fatal malignancy showing a 5% 5-year survival rate, creating an urgent need for new therapeutic targets. Many cancers have high production of reactive oxygen species (ROS), leaving them potentially vulnerable to targeting proteins involved in ROS metabolism. In line with this, we identified Peroxiredoxin 4 (PRDX4) as an essential gene in 26% of pancreatic cell lines by mining functional genomics datasets. PRDX4 is localized in the endoplasmic reticulum (ER) where it metabolizes H2O2. We validated in nine established PCa cell lines and patient derived primary cell lines that depletion of PRDX4 using siRNA or shRNA leads to inhibition of proliferation and cell death in a subset of pancreatic cancer cells. This was accompanied by increased levels of reactive oxygen species (ROS) as measured by flow cytometry. Dual-Depletion of NADPH oxidase 4 (NOX4) and PRDX4 could rescue the cell death phenotype thereby indicating that increase in ROS was a consequence of NOX4 activity. PRDX4 depletion led to focal accumulation of phosphorylated H2AX (γH2AX) in the cellular nuclei, consistent with DNA damage. Phosphorylation of H2AX was exclusively dependent upon activation of the upstream kinase DNA-PKcs. Cells depleted for PRDX4 were also more sensitive to ionizing radiation. Depleting PRDX4 with inducible shRNA in established xenografts inhibited tumor growth. Finally, using transcriptome data accompanying the functional genomics datasets, we identified a 2-gene expression signature that predicts sensitivity to PRDX4 targeting. This study indicates that depletion of PRDX4 causes increased ROS resulting in DNA damage leading to DNA-PKcs activation, inhibition of proliferation and cell death in a subset of pancreatic cancers. PRDX4 is a potential novel therapeutic target that may act synergistically with radiation therapy. Citation Format: Pallavi Jain, Azin Sayad, Erik Mollen, Michael Xie, Kevin Brown, Jason Moffat, David Hedley, Paul Boutros, Bradley Wouters, Marianne Koritzinsky. PRDX4 as a novel target for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 883.