Abstract 3919: Sensitization of pancreatic cancer stem cells to gemcitabine by Chk1 inhibition

We have previously shown that inhibition of Chk1 (checkpoint kinase 1), a key regulator of DNA damage response/repair, sensitizes pancreatic cancer cells and tumors to gemcitabine. However the role of Chk1 inhibition in the sensitivity of pancreatic CSC's (cancer stem cells) to gemcitabine is not known. Pancreatic CSC's have been reported to be resistant to chemo- and radio-therapy via enhanced DNA damage response/repair. Therefore, in the present study we have tested whether inhibition of Chk1 by AZD7762 (AstraZeneca), currently in Phase I clinical trials, would selectively sensitize pancreatic cancer stem cells to gemcitabine. We utilized two patient-derived xenograft models (designated patient J and F) and the previously identified pancreatic CSC markers CD24, CD44, and ESA. Following tumor initiation, NOD/SCID mice were treated with gemcitabine (90mg/kg, Mon & Thu) and/or AZD7762 (20mg/kg, Mon, Tues, Thu, & Fri) for three cycles. At the end of treatment tumors were harvested and the percentage of CD24, CD44 and ESA positive cells was determined. We found that the percentage of CD24, CD44, ESA positive cells was significantly reduced in response to gemcitabine+AZD7762 (1.3 ± 0.17%, p