Downregulation Of Pim-3 Kinase Inhibits Cell Growth And Chemosensitizes Pancreatic Cancer Cells To Gemcitabine

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Pancreatic ductal adenocarcinoma (PDAC) is the most common cancer of the pancreas, comprising over 85% of all cases. PDAC has a relative 1-year survival rate of 24% and a 5-year survival rate of 5%. Recent clinical studies indicate that patients with advanced pancreatic cancer show a 12% tumor response rate after treatment with the chemotherapeutic drug gemcitabine. Even in combination with other chemotherapeutic agents such as erlotinib, survival rates are only increased by a few weeks. Past studies have shown that members of the oncogenic Pim kinase family are aberrantly expressed in a variety of solid tumors, including prostate and pancreatic cancers. Most recently, Pim kinase has been correlated with chemoresistance in prostate cancer cells. Our study aimed to investigate the role of Pim-3 kinase in the chemoresistance of PDAC cancer cells to gemcitabine. We hypothesize that inhibition of Pim-3 will decrease cell growth and sensitize PDAC cells to gemcitabine treatment. Initially, we confirmed by immunohistochemistry and western blot analysis that Pim-3 is aberrantly expressed in PDAC tissues and cell lines, respectively. We found that inhibition of Pim-3 expression by shRNA decreased PDAC cell growth and resulted in an accumulation of cells in G1 or S phase of the cell cycle. Additionally, we demonstrated that PDAC cells expressing Pim-3 shRNA had increased apoptosis after gemcitabine treatment compared to controls. To determine a possible mechanism for this resensitization of PDAC cells to gemcitabine, we measured multidrug resistance (MDR)1 activity in the Pim-3 shRNA cells. We found that inhibition of Pim-3 protein expression in PDAC cells promoted gemcitabine sensitivity, in part, by lowering MDR1 activity. Our results suggest that downregulation of Pim-3 potentiates the efficacy of gemcitabine in combating pancreatic cancer. These findings support the idea that inhibiting Pim kinases, in combination with chemotherapeutic agents, could play an important role in pancreatic cancer treatment by targeting the clinical problem of chemoresistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 256. doi:10.1158/1538-7445.AM2011-256