Combination of RAGE inhibitors and gemcitabine to mitigate chemo‐resistance in pancreatic cancer

Abstract

Pancreatic cancer is currently the fourth leading cause of cancer deaths in the US with a dismal 5‐year survival rate of 7%. Despite several advancements in therapy, gemcitabine remains the standard treatment for pancreatic cancer. However, the modest survival advantage presented by gemcitabine evokes the need for a targeted therapeutic approach in addition to conventional treatment. The Receptor for advanced glycation end‐products (RAGE) is a cell surface receptor which has been demonstrated to be involved in pancreatic cancer progression. RAGE is also reported to facilitate pancreatic tumor cell survival by supporting autophagy and restricting apoptosis. Recent reports have illustrated RAGE as a potential mediator of chemo‐resistance in pancreatic cancer. HMGB1, one of the important ligands of RAGE, is released from necrotic cells upon treatment with gemcitabine. This HMGB1 triggers upregulation of RAGE in the tumor, making it resistant to chemotherapy. We intend to target pancreatic cancer with RAGE inhibitors in combination with gemcitabine to improve survival. We hypothesize that RAGE inhibitors can prevent the interaction between RAGE and its ligands, consequently sensitizing pancreatic cancer for gemcitabine. To accomplish the aim of our study we employed orthotopic mouse model of pancreatic cancer. KPC cells, derived from mice tumors, were implanted in the pancreas of C57BL/6 mice. The mice were divided into four treatment groups: (i) Saline control (ii) Gemcitabine (iii) RAGE inhibitor (anti‐RAGE antibody, IgG2A11) (iv) RAGE inhibitor + gemcitabine. At the end of the study, the tumors obtained from the different treatment groups were assessed for their size, weight and volume. Additionally, the tumors from the four treatment groups were analyzed for the expression of markers of cell proliferation (Ki67), autophagy (LC3), apoptosis (cleaved caspase 3) and cell survival (BCl2) by western blot and immunohistochemistry. We also compared the phosphorylation of ERK1/2 in the tumors from the four treatment groups by western blot. The data showed a statistically significant reduction in tumor weight in mice treated with the combination of anti‐RAGE antibody, IgG2A11 and gemcitabine as compared to the control group. We could also observe a significant decrease in the expression of LC3 and an increase in cleaved caspase 3 in the tumors treated with the combination as compared to the control group. There was also a significant reduction in the phosphorylation of ERK1/2 in tumors treated with anti‐RAGE antibody IgG2A11 and gemcitabine. These results imply that the combination of RAGE inhibitors and gemcitabine can be used as an approach to mitigate chemo‐resistance in pancreatic cancer. Support or Funding Information College of Health Professions at NDSU NIH Grant Number P20 GM109024 from the National Institute of General Medicine (NIGMS) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .