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