Sequential ATR and PARP inhibition overcomes acquired DNA damaging agent resistance in pancreatic ductal adenocarcinoma
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Katharine J Herbert1, Rosie Upstill-Goddard1, Stephan B Dreyer1,2
1Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK.
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.
Insights
Novel sequential treatment with ATR inhibitor ceralasertib and PARP inhibitor olaparib shows promise in overcoming acquired resistance in pancreatic cancer models. This strategy may offer a new therapeutic avenue for patients with pancreatic ductal adenocarcinoma.
Area of Science:
- Oncology
- Cancer Therapeutics
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer.
- Acquired resistance to DNA damaging agents like platinum and PARP inhibitors is a major clinical challenge.
- Novel strategies are urgently needed to overcome treatment resistance in PDAC.
Purpose of the Study:
- To investigate the efficacy of ATR inhibitor ceralasertib and PARP inhibitor olaparib in overcoming acquired resistance in PDAC.
- To explore combination and sequential treatment regimens.
- To understand the molecular mechanisms underlying acquired resistance.
Main Methods:
- Established clinically relevant chemo-resistant PDAC cell lines.
- Utilized synergy scoring, clonogenicity, flow cytometry, and immunofluorescence.
- Performed transcriptomic analysis to identify molecular shifts.
Main Results:
- Acquired resistance involved transcriptomic changes in cell cycle, metabolism, DNA damage response (DDR), and replication stress.
- Combination of ceralasertib and olaparib demonstrated synergy in all resistant models.
- Sequential treatment showed differential efficacy based on DDR proficiency: ceralasertib then olaparib for DDR-proficient, and olaparib first for DDR-deficient models.
Conclusions:
- In vitro evidence supports a novel sequential therapy using ceralasertib and olaparib to overcome acquired resistance in PDAC.
- Sequential regimens warrant clinical investigation to potentially circumvent dose-limiting toxicities of concurrent combinations.
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