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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
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URI: https://cronfa.swan.ac.uk/Record/cronfa63760
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spelling v2 63760 2023-07-01 A Mathematical Model to Investigate the Effects of Ceralasertib and Olaparib in Targeting the Cellular DNA Damage Response Pathway e2bcf0a296532267950a2fc033540ef4 Kira Pugh Kira Pugh true false f23646a94239f673e2a43ebe7397aabd 0000-0002-8372-7349 Gibin Powathil Gibin Powathil true false 2023-07-01 SMA 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. Journal Article Journal of Pharmacology and Experimental Therapeutics 387 1 55 65 American Society for Pharmacology & Experimental Therapeutics (ASPET) 0022-3565 1521-0103 Anti-cancer agents, computer modeling and simulation, DNA damage and repair 1 10 2023 2023-10-01 10.1124/jpet.122.001558 http://dx.doi.org/10.1124/jpet.122.001558 COLLEGE NANME Mathematics COLLEGE CODE SMA Swansea University Other KP is supported by EPSRC DTP via Swansea University [Grant EP/T517987/1] 2023-12-08T12:53:31.8058774 2023-07-01T10:28:19.6511089 Faculty of Science and Engineering School of Mathematics and Computer Science - Mathematics Kira Pugh 1 Michael Davies 2 Gibin Powathil 0000-0002-8372-7349 3 63760__28017__12cc6fc4091641e089efd848d3b814c4.pdf jpet.122.001558.full.pdf 2023-07-01T10:33:33.7404782 Output 1319492 application/pdf Proof true Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title A Mathematical Model to Investigate the Effects of Ceralasertib and Olaparib in Targeting the Cellular DNA Damage Response Pathway
spellingShingle A Mathematical Model to Investigate the Effects of Ceralasertib and Olaparib in Targeting the Cellular DNA Damage Response Pathway
Kira Pugh
Gibin Powathil
title_short A Mathematical Model to Investigate the Effects of Ceralasertib and Olaparib in Targeting the Cellular DNA Damage Response Pathway
title_full A Mathematical Model to Investigate the Effects of Ceralasertib and Olaparib in Targeting the Cellular DNA Damage Response Pathway
title_fullStr A Mathematical Model to Investigate the Effects of Ceralasertib and Olaparib in Targeting the Cellular DNA Damage Response Pathway
title_full_unstemmed A Mathematical Model to Investigate the Effects of Ceralasertib and Olaparib in Targeting the Cellular DNA Damage Response Pathway
title_sort A Mathematical Model to Investigate the Effects of Ceralasertib and Olaparib in Targeting the Cellular DNA Damage Response Pathway
author_id_str_mv e2bcf0a296532267950a2fc033540ef4
f23646a94239f673e2a43ebe7397aabd
author_id_fullname_str_mv e2bcf0a296532267950a2fc033540ef4_***_Kira Pugh
f23646a94239f673e2a43ebe7397aabd_***_Gibin Powathil
author Kira Pugh
Gibin Powathil
author2 Kira Pugh
Michael Davies
Gibin Powathil
format Journal article
container_title Journal of Pharmacology and Experimental Therapeutics
container_volume 387
container_issue 1
container_start_page 55
publishDate 2023
institution Swansea University
issn 0022-3565
1521-0103
doi_str_mv 10.1124/jpet.122.001558
publisher American Society for Pharmacology & Experimental Therapeutics (ASPET)
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Mathematics and Computer Science - Mathematics{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Mathematics and Computer Science - Mathematics
url http://dx.doi.org/10.1124/jpet.122.001558
document_store_str 1
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description 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.
published_date 2023-10-01T12:53:32Z
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