RT Journal Article
SR Electronic
T1 A Mathematical Model to Investigate the Effects of Ceralasertib and Olaparib in Targeting the Cellular DNA Damage Response Pathway
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 55
OP 65
DO 10.1124/jpet.122.001558
VO 387
IS 1
A1 Pugh, Kira
A1 Davies, Michael
A1 Powathil, Gibin
YR 2023
UL http://jpet.aspetjournals.org/content/387/1/55.abstract
AB The ataxia-telangiectasia and Rad3-related (ATR) inhibitor ceralasertib and the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib have shown synergistic activity, in vitro, in the FaDu ATM-knockout cell line. It was found that combining these drugs with lower doses and for shorter treatment periods induced greater or equal toxicity in cancer cells than using either as a single agent. Here, we developed a biologically motivated mathematical model governed by a set of ordinary differential equations, considering the cell cycle–specific interactions of olaparib and ceralasertib. By exploring a range of different possible drug mechanisms, we have studied the effects of their combination as well as which drug interactions are the most prominent. After careful model selection, the model was calibrated and compared with relevant experimental data. We have used this developed model further to investigate other doses of olaparib and ceralasertib in combination, which can be potentially helpful in exploring optimized dosage and delivery.SIGNIFICANCE STATEMENT Drugs that target cellular DNA damage repair pathways are now being used as a new way to maximize the effect of multimodality treatments such as radiotherapy. Here, we develop a mathematical model to investigate the effects of ceralasertib and olaparib, two drugs that target DNA damage response pathways.