Abstract
BackgroundAlthough pancreatic ductal adenocarcinomas (PDAs) widely express HER2, the expression level is generally low. If HER2 expression in PDA cells could be enhanced by treatment with a given agent, then combination therapy with that agent and trastuzumab emtansine (T-DM1), a chemotherapeutic agent that is a conjugate of trastuzumab, might lead to significant antitumor effects against PDA.MethodsCell proliferation was examined by spectrophotometry. HER2 expression was examined by flow cytometry, immunoblot and quantitative reverse transcription polymerase chain reaction. T-DM1 binding to cells was examined by flow cytometry and enzyme-linked immunosorbent assay.ResultsOut of 5 tested human PDA cell lines, including MIA PaCa-2, three showed increases in HER2 expression after gemcitabine (GEM) treatment. The binding of T-DM1 to GEM-treated MIA PaCa-2 cells was higher than to untreated MIA PaCa-2 cells. Treatment with GEM and T-DM1 showed synergic cytotoxic effects on MIA PaCa-2 cells in vitro. Cells in the G2M phase of the cell cycle were retained after GEM treatment and showed higher levels of HER2 expression, possibly contributing to the synergic effect of GEM and T-DM1.ConclusionsCombined treatment with GEM and T-DM1 might confer a potent therapeutic modality against PDA as a result of GEM-mediated HER2 up-regulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1772-1) contains supplementary material, which is available to authorized users.
Highlights
Pancreatic ductal adenocarcinomas (PDAs) widely express Human epidermal growth factor receptor 2 (HER2), the expression level is generally low
The augmentation of HER2 expression in MIA PaCa-2 cells following GEM treatment was examined by immunoblot analysis
In the present study, we demonstrated that the expression of HER2 in several human PDA cell lines, including in MIA PaCa-2, was enhanced by short-term treatment with GEM
Summary
Pancreatic ductal adenocarcinomas (PDAs) widely express HER2, the expression level is generally low. If HER2 expression in PDA cells could be enhanced by treatment with a given agent, combination therapy with that agent and trastuzumab emtansine (T-DM1), a chemotherapeutic agent that is a conjugate of trastuzumab, might lead to significant antitumor effects against PDA. The treatment of HER2-overexpressing breast or gastric cancer patients with trastuzumab in combination with chemotherapeutic agents is being evaluated in phase III clinical studies and is more effective than standard chemotherapy [7, 8]. Trastuzumab treatment against human PDA cells has shown significant antitumor activity in basic in vivo and in vitro studies, the combined treatment of gemcitabine (GEM) or capecitabine with trastuzumab against metastatic PDA did not result in improved progressionfree survival or overall survival, possibly because the expression and gene amplification of HER2 in PDAs were generally lower than in breast cancer [14, 15]
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