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BKM120 sensitizes BRCA-proficient triple negative breast cancer cells to olaparib through regulating FOXM1 and Exo1 expression
Scientific Reports ( IF 3.8 ) Pub Date : 2021-02-26 , DOI: 10.1038/s41598-021-82990-y
Yu Li 1 , Yuantao Wang 2 , Wanpeng Zhang 2 , Xinchen Wang 1 , Lu Chen 1 , Shuping Wang 1
Affiliation  

Poly (ADP-ribose) polymerase (PARP) inhibitors offer a significant clinical benefit for triple-negative breast cancers (TNBCs) with BRCA1/2 mutation. However, the narrow clinical indication limits the development of PARP inhibitors. Phosphoinositide 3-kinase (PI3K) inhibition sensitizes BRCA-proficient TNBC to PARP inhibition, which broadens the indication of PARP inhibitors. Previously researches have reported that PI3K inhibition induced the defect of homologous recombination (HR) mediated repair by downregulating the expression of BRCA1/2 and Rad51. However, the mechanism for their synergistic effects in the treatment of TNBC is still unclear. Herein, we focused on DNA damage, DNA single-strand breaks (SSBs) repair and DNA double-strand breaks (DSBs) repair three aspects to investigate the mechanism of dual PI3K and PARP inhibition in DNA damage response. We found that dual PI3K and PARP inhibition with BKM120 and olaparib significantly reduced the proliferation of BRCA-proficient TNBC cell lines MDA-MB-231 and MDA231-LM2. BKM120 increased cellular ROS to cause DNA oxidative damage. Olaparib resulted in concomitant gain of PARP1, forkhead box M1 (FOXM1) and Exonuclease 1 (Exo1) while inhibited the activity of PARP. BKM120 downregulated the expression of PARP1 and PARP2 to assist olaparib in blocking PARP mediated repair of DNA SSBs. Meanwhile, BKM120 inhibited the expression of BRAC1/2 and Rad51/52 to block HR mediated repair through the PI3K/Akt/NFκB/c-Myc signaling pathway and PI3K/Akt/ FOXM1/Exo1 signaling pathway. BKM120 induced HR deficiency expanded the application of olaparib to HR proficient TNBCs. Our findings proved that PI3K inhibition impaired the repair of both DNA SSBs and DNA DSBs. FOXM1 and Exo1 are novel therapeutic targets that serves important roles in DNA damage response.



中文翻译:


BKM120 通过调节 FOXM1 和 Exo1 表达使 BRCA 熟练的三阴性乳腺癌细胞对奥拉帕尼敏感



聚 (ADP-核糖) 聚合酶 (PARP) 抑制剂为具有 BRCA1/2 突变的三阴性乳腺癌 (TNBC) 提供显着的临床益处。然而,狭窄的临床适应症限制了PARP抑制剂的发展。磷酸肌醇 3-激酶 (PI3K) 抑制使 BRCA 丰富的 TNBC 对 PARP 抑制敏感,从而拓宽了 PARP 抑制剂的适应症。此前有研究报道,PI3K抑制通过下调BRCA1/2和Rad51的表达来诱导同源重组(HR)介导的修复缺陷。然而,它们在治疗TNBC中的协同作用机制仍不清楚。在此,我们重点从DNA损伤、DNA单链断裂(SSBs)修复和DNA双链断裂(DSBs)修复三个方面探讨PI3K和PARP双重抑制在DNA损伤反应中的机制。我们发现,BKM120 和奥拉帕尼的双重 PI3K 和 PARP 抑制显着降低了 BRCA 熟练的 TNBC 细胞系 MDA-MB-231 和 MDA231-LM2 的增殖。 BKM120 增加细胞 ROS 导致 DNA 氧化损伤。奥拉帕尼导致 PARP1、叉头盒 M1 (FOXM1) 和核酸外切酶 1 (Exo1) 的同时增加,同时抑制 PARP 的活性。 BKM120 下调 PARP1 和 PARP2 的表达,以协助奥拉帕尼阻断 PARP 介导的 DNA SSB 修复。同时,BKM120通过PI3K/Akt/NFκB/c-Myc信号通路和PI3K/Akt/FOXM1/Exo1信号通路抑制BRAC1/2和Rad51/52的表达,从而阻断HR介导的修复。 BKM120 诱导的 HR 缺陷扩大了奥拉帕尼在 HR 熟练的 TNBC 中的应用。我们的研究结果证明,PI3K 抑制会损害 DNA SSB 和 DNA DSB 的修复。 FOXM1 和 Exo1 是新型治疗靶点,在 DNA 损伤反应中发挥重要作用。

更新日期:2021-02-26
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