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A Mathematical Model to Investigate the Effects of Ceralasertib and Olaparib in Targeting the Cellular DNA Damage Response Pathway

Kira Pugh, Michael Davies, Gibin Powathil Orcid Logo

Journal of Pharmacology and Experimental Therapeutics, Volume: 387, Issue: 1, Pages: 55 - 65

Swansea University Authors: Kira Pugh, Gibin Powathil Orcid Logo

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DOI (Published version): 10.1124/jpet.122.001558

Abstract

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-KO cell line. It was found that combining these drugs with lower doses and for shorter treatment periods i...

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Published in: Journal of Pharmacology and Experimental Therapeutics
ISSN: 0022-3565 1521-0103
Published: American Society for Pharmacology & Experimental Therapeutics (ASPET) 2023
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa63760
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Abstract: 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-KO 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 develop 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 to 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 optimised dosage and delivery.
Keywords: Anti-cancer agents, computer modeling and simulation, DNA damage and repair
College: Faculty of Science and Engineering
Funders: KP is supported by EPSRC DTP via Swansea University [Grant EP/T517987/1]
Issue: 1
Start Page: 55
End Page: 65

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