State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 211198, Nanjing, China.
Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
Cell Death Dis. 2021 Dec 8;12(12):1138. doi: 10.1038/s41419-021-04434-9.
Inducing homologous-recombination (HR) deficiency is an effective strategy to broaden the indications of PARP inhibitors in the treatment of triple-negative breast cancer (TNBC). Herein, we find that repression of the oncogenic transcription factor FOXM1 using FOXM1 shRNA or FOXM1 inhibitor FDI-6 can sensitize BRCA-proficient TNBC to PARP inhibitor Olaparib in vitro and in vivo. Mechanistic studies show that Olaparib causes adaptive resistance by arresting the cell cycle at S and G/M phases for HR repair, increasing the expression of CDK6, CCND1, CDK1, CCNA1, CCNB1, and CDC25B to promote cell cycle progression, and inducing the overexpression of FOXM1, PARP1/2, BRCA1/2, and Rad51 to activate precise repair of damaged DNA. FDI-6 inhibits the expression of FOXM1, PARP1/2, and genes involved in cell cycle control and DNA damage repair to sensitize TNBC cells to Olaparib by blocking cell cycle progression and DNA damage repair. Simultaneously targeting FOXM1 and PARP1/2 is an innovative therapy for more patients with TNBC.
诱导同源重组（HR）缺陷是拓宽 PARP 抑制剂在三阴性乳腺癌（TNBC）治疗中的适应证的有效策略。在此，我们发现使用 FOXM1 shRNA 或 FOXM1 抑制剂 FDI-6 抑制致癌转录因子 FOXM1，可以在体外和体内增强 BRCA 功能正常的 TNBC 对 PARP 抑制剂奥拉帕利的敏感性。机制研究表明，奥拉帕利通过将细胞周期阻滞在 S 和 G2/M 期进行 HR 修复，增加 CDK6、CCND1、CDK1、CCNA1、CCNB1 和 CDC25B 的表达来促进细胞周期进程，从而导致适应性耐药，并诱导 FOXM1、PARP1/2、BRCA1/2 和 Rad51 的过表达，以激活受损 DNA 的精确修复。FDI-6 通过阻断细胞周期进程和 DNA 损伤修复来抑制 FOXM1、PARP1/2 以及参与细胞周期控制和 DNA 损伤修复的基因的表达，从而增强 TNBC 细胞对奥拉帕利的敏感性。同时靶向 FOXM1 和 PARP1/2 是为更多 TNBC 患者提供的一种创新疗法。
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