Background/Objectives: Clinical use of poly(ADP-ribose) polymerase inhibitors (PARPis) against metastatic high-grade serous ovarian carcinoma (HGSOC) is limited to cases with deficient a homologous recombination (HR). Our objective was to determine whether the impairment of the fractalkine receptor (CX3CR1) could sensitize HR-proficient cases to PARPis. Methods: The efficacy of a dual drug combination, including AZD8797, an inhibitor of CX3CR1, and several PARPis was examined using cell lines and xenograft models. Results: The effectiveness of PARPis and AZD8797 drug combinations ranged from additive to strongly synergistic. Olaparib was synergistic with AZD8797 in OVCAR-4, Caov-3, and OHSAHO. Niraparib and AZD8797 produced synergy in OVCAR-4 and ES2. Rucaparib and AZD8797 were strongly synergistic in Caov-3 and OVSAHO. Veliparib was strongly synergistic with AZD8797 in OVCAR-4 and Caov-3. Notably, a combination of veliparib and AZD8797 produced a strong synergistic effect in a xenograft model. Conclusions: While the exact mechanisms determining the nature of the PARPis and AZD8797 interaction remain to be uncovered, our data indicate that, in a subset of models, selected PARPis strongly synergize with the inhibition of CX3CR1, suggesting a potential therapeutic opportunity.
背景/目的：聚腺苷二磷酸核糖聚合酶抑制剂（PARPis）在临床中用于治疗转移性高级别浆液性卵巢癌（HGSOC）时，仅限于同源重组（HR）缺陷的病例。本研究旨在探讨抑制趋化因子受体（CX3CR1）是否能使HR功能正常的病例对PARPis敏感。方法：通过细胞系和异种移植模型，评估了包含CX3CR1抑制剂AZD8797与多种PARPis的双药联合方案的疗效。结果：PARPis与AZD8797的联合效果从相加效应到强协同效应不等。奥拉帕尼与AZD8797在OVCAR-4、Caov-3和OHSAHO细胞中表现出协同作用；尼拉帕尼与AZD8797在OVCAR-4和ES2细胞中产生协同效应；鲁卡帕尼与AZD8797在Caov-3和OVSAHO细胞中呈现强协同作用；维利帕尼与AZD8797在OVCAR-4和Caov-3细胞中具有强协同效应。值得注意的是，在异种移植模型中，维利帕尼与AZD8797的联合应用产生了显著的协同效果。结论：尽管决定PARPis与AZD8797相互作用性质的具体机制尚待阐明，但我们的数据表明，在部分模型中，特定的PARPis与CX3CR1抑制具有强协同作用，这提示了一种潜在的治疗策略。
Dual Targeting of CX3CR1 and PARP in Models of High-Grade Serous Ovarian Carcinoma
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