Sequential ATR and PARP inhibition overcomes acquired DNA damaging agent resistance in pancreatic ductal adenocarcinoma.
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Embargo End Date
ICR Authors
Authors
Herbert, KJ
Upstill-Goddard, R
Dreyer, SB
Rebus, S
Pilarsky, C
Debabrata, M
Lord, CJ
Biankin, AV
Froeling, FEM
Chang, DK
Upstill-Goddard, R
Dreyer, SB
Rebus, S
Pilarsky, C
Debabrata, M
Lord, CJ
Biankin, AV
Froeling, FEM
Chang, DK
Document Type
Journal Article
Date
2025-08-24
Date Accepted
2025-05-01
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.
Citation
British Journal of Cancer, 2025, 133 (3), pp. 381 - 393
Source Title
British Journal of Cancer
Publisher
SPRINGERNATURE
ISSN
0007-0920
eISSN
1532-1827
Collections
Research Team
Precision Oncology Lord