PT  - JOURNAL ARTICLE
AU  - Pugh, Kira
AU  - Davies, Michael
AU  - Powathil, Gibin
TI  - A Mathematical Model to Investigate the Effects of Ceralasertib and Olaparib in Targeting the Cellular DNA Damage Response Pathway
AID  - 10.1124/jpet.122.001558
DP  - 2023 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 55--65
VI  - 387
IP  - 1
4099  - http://jpet.aspetjournals.org/content/387/1/55.short
4100  - http://jpet.aspetjournals.org/content/387/1/55.full
SO  - J Pharmacol Exp Ther2023 Oct 01; 387
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.