FDI-6 and olaparib synergistically inhibit the growth of pancreatic cancer by repressing BUB1, BRCA1 and CDC25A signaling pathways. (January 2022) - Wu, Shi-Qi
Abstract: 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. Graphical Abstract: ga1 Highlights: FID-6 and Olaparib synergistically inhibit the expression of FOXM1 and PARP1/2. FOXM1 directly interacts with PARP1. Olaparib induces the acceleration of cell mitosis and recovery of DNA repair. FID-6 reverses Olaparib-induced adaptive resistance. BUB1, CDC25A and BRCA1 are the key genes regulated by FOXM1 and PARP1.