Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 211198 Nanjing, China.
Pharmacol Res. 2022 Jan;175:106040. doi: 10.1016/j.phrs.2021.106040. Epub 2021 Dec 22.
Inducing homologous recombination (HR) deficiency is a promising strategy to broaden the indication of PARP1/2 inhibitors in pancreatic cancer treatment. In addition to inhibition kinases, repression of the transcriptional function of FOXM1 has been reported to inhibit HR-mediated DNA repair. We found that FOXM1 inhibitor FDI-6 and PARP1/2 inhibitor Olaparib synergistically inhibited the malignant growth of pancreatic cancer cells in vitro and in vivo. The results of bioinformatic analysis and mechanistic study showed that FOXM1 directly interacted with PARP1. Olaparib induced the feedback overexpression of PARP1/2, FOXM1, CDC25A, CCND1, CDK1, CCNA2, CCNB1, CDC25B, BRCA1/2 and Rad51 to promote the acceleration of cell mitosis and recovery of DNA repair, which caused the generation of adaptive resistance. FDI-6 reversed Olaparib-induced adaptive resistance and inhibited cell cycle progression and DNA damage repair by repressing the expression of FOXM1, PARP1/2, BUB1, CDC25A, BRCA1 and other genes-involved in cell cycle control and DNA damage repair. We believe that targeting FOXM1 and PARP1/2 is a promising combination therapy for pancreatic cancer without HR deficiency.
诱导同源重组 (HR) 缺陷是拓宽 PARP1/2 抑制剂在胰腺癌治疗中应用的有前途的策略。除了抑制激酶外，还报道了抑制 FOXM1 的转录功能可抑制 HR 介导的 DNA 修复。我们发现 FOXM1 抑制剂 FDI-6 和 PARP1/2 抑制剂奥拉帕利在体外和体内协同抑制胰腺癌细胞的恶性生长。生物信息学分析和机制研究的结果表明，FOXM1 与 PARP1 直接相互作用。奥拉帕利诱导 PARP1/2、FOXM1、CDC25A、CCND1、CDK1、CCNA2、CCNB1、CDC25B、BRCA1/2 和 Rad51 的反馈过表达，以促进细胞有丝分裂的加速和 DNA 修复的恢复，从而产生适应性耐药。FDI-6 逆转奥拉帕利诱导的适应性耐药，并通过抑制 FOXM1、PARP1/2、BUB1、CDC25A、BRCA1 和其他参与细胞周期控制和 DNA 损伤修复的基因的表达来抑制细胞周期进程和 DNA 损伤修复。我们相信，针对 FOXM1 和 PARP1/2 的联合治疗是一种有前途的治疗 HR 缺陷型胰腺癌的方法。
