Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Oncogene. 2021 Jun;40(22):3845-3858. doi: 10.1038/s41388-021-01788-4. Epub 2021 May 8.
PARP inhibitors (PARPi) are efficacious in treating high-grade serous ovarian cancer (HG-SOC) with homologous recombination (HR) deficiency. However, they exhibit suboptimal efficiency in HR-proficient cancers. Here, we found that the expression of CCAAT/enhancer-binding protein β (C/EBPβ), a transcription factor, was inversely correlated with PARPi sensitivity in vitro and in vivo, both in HR-proficient condition. High C/EBPβ expression enhanced PARPi tolerance; PARPi treatment in turn induced C/EBPβ expression. C/EBPβ directly targeted and upregulated multiple HR genes (BRCA1, BRIP1, BRIT1, and RAD51), thereby inducing restoration of HR capacity and mediating acquired PARPi resistance. C/EBPβ is a key regulator of the HR pathway and an indicator of PARPi responsiveness. Targeting C/EBPβ could induce HR deficiency and rescue PARPi sensitivity accordingly. Our findings indicate that HR-proficient patients may benefit from PARPi via targeting C/EBPβ, and C/EBPβ expression levels enable predicting and tracking PARPi responsiveness during treatment.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂（PARPi）在治疗同源重组（HR）缺陷的高级别浆液性卵巢癌（HG-SOC）方面非常有效。然而，它们在 HR 有效的癌症中表现出不佳的效率。在这里，我们发现转录因子 CCAAT/增强子结合蛋白 β（C/EBPβ）的表达与体外和体内 HR 有效的条件下 PARPi 敏感性呈负相关。高 C/EBPβ 表达增强了 PARPi 耐受性；PARPi 治疗反过来又诱导了 C/EBPβ 的表达。C/EBPβ 直接靶向并上调多个 HR 基因（BRCA1、BRIP1、BRIT1 和 RAD51），从而诱导 HR 能力的恢复，并介导获得性 PARPi 耐药性。C/EBPβ 是 HR 通路的关键调节剂，也是 PARPi 反应性的指标。靶向 C/EBPβ 可以诱导 HR 缺陷，并相应地恢复 PARPi 敏感性。我们的研究结果表明，HR 有效的患者可能通过靶向 C/EBPβ 从 PARPi 中受益，并且 C/EBPβ 表达水平可以在治疗期间预测和跟踪 PARPi 反应性。
