Herbert Katharine J, Upstill-Goddard Rosie, Dreyer Stephan B, Rebus Selma, Pilarsky Christian, Debabrata Mukhopadhyay, Lord Christopher J, Biankin Andrew V, Froeling Fieke E M, Chang David K
Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK.
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, G4 0SF, UK.
Br J Cancer. 2025 May 29. doi: 10.1038/s41416-025-03051-z.
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.
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.
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.
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.
胰腺导管腺癌（PDAC）仍然是最致命的癌症。虽然铂类和PARP抑制剂等DNA损伤剂已带来临床益处，但总会出现获得性耐药。因此，迫切需要新的治疗策略来克服获得性耐药。
通过长期暴露于化疗药物，在源自PDAC患者的细胞系中实现临床相关耐药。采用协同评分、克隆形成、流式细胞术、免疫荧光和转录组分析来研究ATR（西拉司他）和PARP（奥拉帕利）抑制剂克服获得性耐药的疗效。
获得性耐药与细胞周期检查点调控、代谢控制、DNA损伤反应（DDR）、程序性细胞死亡和复制应激反应中的转录组变化有关。西拉司他和奥拉帕利联合治疗在所有获得性耐药模型中均具有协同作用。在DDR功能正常的模型中，低剂量时先使用西拉司他再使用奥拉帕利非常有效，而DDR缺陷模型先使用奥拉帕利治疗反应更好。
我们提供了体外证据，证明了一种新的治疗策略，即通过先后使用西拉司他和奥拉帕利来克服PDAC对PARP抑制剂和铂类的获得性耐药。应在临床上研究序贯方案，以规避联合使用时出现的剂量限制毒性。
