Abstract LB-22: Gemcitabine resistance is associated with EMT phenotype along with expression of cancer stem cell markers and a specific miRNA profile in the human pancreatic cancer cell line BxPC3

Abstract

Abstract Despite new therapeutic strategies, human pancreatic ductal adenocarcinomas (PDAC) remain one of the greatest oncological challenges, as the rate of incidence almost equals the rate of mortality with a 5-year survival of less than 5%. Gemcitabine is the standard therapy for PDAC and is mostly used alone or in combination with an EGFR inhibitor. While tumors respond to Gemcitabine treatment initially, they generally develop chemoresistance. A thorough understanding of molecular events that promote resistance against Gemcitabine may identify pathways that can be efficiently targeted to reverse chemoresistance. A cell line model resistant to Gemcitabine was generated by transiently exposing BxPC3 cells to increasing concentrations of Gemcitabine. This Gemcitabine resistant cell line, BxPC3-GzR, was compared with untreated BxPC3 control cells. BxPC3-GzR cells showed properties of undergoing epithelial to mesenchymal transition (EMT) and these included a spindle shaped morphology, an increase in expression of vimentin and a decrease in expression of E-cadherin. BxPC3-GzR cells also showed an increase of expression of CD44 and in expression of phosphorylated STAT3TY705, which are characteristic of cancer stem cells. BxPC3 and BxPC3-GzR where further compared by microarray analyses for expression of micro-RNAs (miRNAs). BxPC3-GzR cells showed a specific miRNA expression profile (9 positively and 8 negatively regulated). Thus far seven of eight miRNAs identified as altered in BxPC3-GzR cells were validated by real-time RT-PCR (miR-15b, miR-21, miR-100, miRNA -125b, miRNA-155, miRNA-205 and miRNA-455-3p). These studies suggest that Gemcitabine treatment of PDAC selects for a resistant population of tumor cells that have a mesenchymal/stem cell-like phenotype and that express a distinct miRNA profile. Targeting these miRNAs may provide novel targets for restoring or enhancing anti-tumor response of Gemcitabine. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-22. doi:1538-7445.AM2012-LB-22