Sequential ATR and PARP inhibition overcomes acquired DNA damaging agent resistance in pancreatic ductal adenocarcinoma
Herbert KJ, Upstill-Goddard R, Dreyer SB, Rebus S, Pilarsky C, Debabrata M, Lord CJ, Biankin AV, Froeling FE, Chang DK (2025)
Publication Type: Journal article
Publication year: 2025
Journal
Article Number: 743908
DOI: 10.1038/s41416-025-03051-z
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) remains the most lethal cancer. While DNA damaging agents such as platinum and PARP inhibitors have derived clinical benefits, acquired resistance invariably develops. Hence there is an urgent need for novel therapeutic strategies to overcome acquired resistance. Methods: Clinically relevant resistance in PDAC patient-derived cell lines was achieved by extended exposure to chemotherapy agents. Synergy scoring, clonogenicity, flow cytometry, immunofluorescence, and transcriptomic analysis were used to investigate the efficacy of ATR (ceralasertib) and PARP (olaparib) inhibitors in overcoming acquired resistance. Results: Acquired resistance was associated with transcriptomic shifts in cell cycle checkpoint regulation, metabolic control, DNA damage response (DDR), programmed cell death, and the replication stress response. Combination treatment with ceralasertib, and olaparib was synergistic in all models of acquired resistance. Sequential use of ceralasertib prior to olaparib was highly effective at low dose for DDR proficient models, whereas DDR deficient models responded better with olaparib treatment first. Conclusions: We provide in vitro evidence of a novel therapeutic strategy to overcome acquired resistance to PARP inhibitor and platinum in PDAC, using sequential exposure to ceralasertib and olaparib. A sequential regimen should be investigated clinically to circumvent dose limiting toxicity seen in concurrent combinations.
Authors with CRIS profile
Involved external institutions
University of Glasgow
United Kingdom (GB)
Mayo Clinic College of Medicine and Science (MCCMS)
United States (USA) (US)
The Institute of Cancer Research (ICR)
United Kingdom (GB)
United Kingdom (GB)
Mayo Clinic College of Medicine and Science (MCCMS)
United States (USA) (US)
The Institute of Cancer Research (ICR)
United Kingdom (GB)
How to cite
APA:
Herbert, K.J., Upstill-Goddard, R., Dreyer, S.B., Rebus, S., Pilarsky, C., Debabrata, M.,... Chang, D.K. (2025). Sequential ATR and PARP inhibition overcomes acquired DNA damaging agent resistance in pancreatic ductal adenocarcinoma. British Journal of Cancer. https://doi.org/10.1038/s41416-025-03051-z
MLA:
Herbert, Katharine J., et al. "Sequential ATR and PARP inhibition overcomes acquired DNA damaging agent resistance in pancreatic ductal adenocarcinoma." British Journal of Cancer (2025).
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