Correlation of gemcitabine sensitization by Chk1 inhibition with p53 status

AbstractsChk1 inhibition can selectively improve gemcitabine sensitivity in p53-deficient cells by checkpoints abrogation throughout the cell cycle. However, the dependency of p53 status is still controversial for predicting the priority of such synergy. This study aimed at expounding the differential therapeutic properties of gemcitabine sensitization by Chk1 inhibition potentially affected by p53 status. We introduced wild-type and hotspot mutant p53 in p53-null H1299 cells, and quantified combination of gemcitabine with two Chk1 inhibitors using Chou-Talalay method. As a result, depletion of p53 preferentially produced synergistic effects. Wild-type and mutant p53 also conferred drug synergy but gradually showed compromised potency of growth inhibition. These data provide increased evidence that p53 status is a weak predictor for identifying an effective synergy, but genetic loss of p53 is relatively favorable for combination treatment. Further efforts on validation in more cell lines and clinical models could improve the predictive validity in this study.