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• W2760480006 abstract "2460 The diagnosis of pancreatic cancer confers a grim prognosis that has changed little over the last 30 years. Although gemcitabine remains the cornerstone of chemotherapy in pancreatic cancer, its efficacy remains limited by the rapid development of tumor cell resistance which may involve redundant chemoresistance mechanisms and/or mesenchymal phenotypes. Utilizing two gemcitabine resistant pancreatic cancer cell lines previously isolated in our lab, the purpose of this study was to: 1) characterize the molecular mechanisms of gemcitabine resistance; 2) determine if common phenotypes and gene expression patterns could predict resistance; and 3) determine if gemcitabine resistance confers global resistance to other chemotherapeutic agents. For these studies, two gemcitabine-sensitive pancreatic cancer cell lines, ASPC-1 and L3.6pl, were maintained in increasing levels of gemcitabine until they developed stable resistance to supratherapeutic concentrations. Common phenotypic features were examined, including markers of epithelial-to-mesenchymal transition (EMT), stem cell marker expression, and sensitivity to oxaliplatin, dasatinib, and XL820 (c-Met inhibitor). As we reported previously, both resistant cell lines displayed hallmarks of EMT including fibroblast-like morphology, increased migration and invasion, increased vimentin, decreased E-cadherin expression, and increased nuclear expression of Twist. To validate these EMT findings, we examined EMT properties of naturally occurring sensitive and resistant lines, including Panc1, Miapaca2, BxPC3, MPANC96, CFPAC1, SU8686, HS766T, and HPDE. We demonstrated that in most cell lines, increased vimentin and decreased E cadherin (EMT characteristics) predicted resistance. We also sought to determine whether the more mesenchymal of our phenotypes conferred resistance to other chemotherapy agents. Both L3.6pl and L3.6plGR were equally sensitive to oxaliplatin. In addition, resistant L3.6pl cells demonstrated increased sensitivity to both dasatinib and XL820. As c-Met is activated in resistant cells, the latter finding suggests c-Met inhibition may sensitize cells to gemcitabine. Lastly, we examined PTEN, a gene product implicated in the self-renewal of cancer stem cells and, in turn, gemcitabine resistance. Relative to parental cells, both resistant lines exhibited decreased expression of PTEN and activation of the PI3K/Akt axis. These findings suggest a potential mechanism of gemcitabine resistance common to our phenotype. Thus, we conclude that PTEN expression and mediators of EMT may be important in the development and maintenance of gemcitabine phenotypes. Further, the sensitivity of the L3.6pl gemcitabine resistant phenotype to tyrosine kinase inhibitors may indicate reliance upon alternate survival elements in conjunction with the development of gemcitabine resistance." @default.
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• W2760480006 date "2008-05-01" @default.
• W2760480006 modified "2023-09-23" @default.
• W2760480006 title "Gemcitabine resistance in cultured pancreatic tumor cells is associated with down regulation of PTEN and a mesenchymal phenotype" @default.
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