Sensitization of Pancreatic Cancer Stem Cells to Gemcitabine by Chk1 Inhibition

摘要: Checkpoint kinase 1 (Chk1) inhibition sensitizes pancreatic cancer cells and tumors to gemcitabine. We hypothesized that Chk1 would sensitize stem tested this hypothesis by using two patient-derived xenograft models (designated J F) the cell markers CD24, CD44, ESA. determined percentage of marker-positive their tumor-initiating capacity (by limiting dilution assays) after treatment with gemcitabine inhibitor, AZD7762. found were significantly reduced combination In addition, secondary tumor initiation was delayed in response primary + AZD7762 compared control, gemcitabine, or alone. Furthermore, for same number implanted from gemcitabine- versus AZD7762-treated tumors, at 10 weeks 83% 43%, respectively. also pS345 Chk1, which is a measure DNA damage, induced but not marker-negative cells. These data demonstrate reduces both finding Chk1-mediated damage greater than non-stem suggests may selectively thus making potential therapeutic target improving therapy.