Although human pancreatic cancer (PC) frequently expresses human epidermal growth factor receptor type 2 (HER2), Trastuzumab has not provided sufficient therapeutic effect on PC probably due to low HER2 expression level. Recently we discovered HER2 expression of human PC cell lines was enhanced by gemcitabine (GEM) treatment. Furthermore, Trastuzumab Emtansine (T-DM1), Trastuzumab conjugated with a cytotoxic agent, showed promising results in breast cancer therapy. We investigated the possibility of new molecular targeting therapy against PC by combined treatment with GEM and T-DM1.
[Materials and Methods]
HER2 expression was analyzed by quantitative Real Time-PCR, western blotting and flowcytometry. The cell proliferation was examined by spectrophotometry using the counting reagents. T-DM1 was provided by Genentech Inc. T-DM1 bindinig to HER2 on PC cell surface was analyzed by flowcytometry.
GEM treatment enhanced HER2 expression at around two fold in three out of five human PC cell lines. GEM was the most potent agent to enhance HER2 expression of PC cells among the standard chemotherapeutic agents for PC treatment. T-DM1 binding to HER2 on GEM-treated MiaPaca-2 cells was increased in accordance with the up-regulation of HER2 expression. Combined treatment with GEM and T-DM1 synergistically inhibited the cell growth of MiaPaca-2, and this cytotoxic effect was inhibited by adding to Trastuzumab which did not show direct cytotoxic activity to PC cells.
GEM treatment enhances HER2 expression of PC cells which promotes T-DM1 binding to HER2 on PC cells. Combined treatment with GEM and T-DM1 might become a promising modality against HER2 positive PC.
Citation Format: Shin Kan, Shigeo Koido, Masato Okamoto, Kazumi Hayashi, Masaki Ito, Yuko Kamata, Hideo Komita, Eijiro Nagasaki, Sadamu Homma. HER2 upregulation induced by gemcitabine treatment augments antitumor effect of trastuzumab emtansine against pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1685. doi:10.1158/1538-7445.AM2014-1685