BKM120 sensitizes BRCA-proficient triple negative breast cancer cells to olaparib through regulating FOXM1 and Exo1 expression

Abstract

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.

Screening of DNA Damage Repair Genes Involved in the Prognosis of Triple-Negative Breast Cancer Patients Based on Bioinformatics

“…Exonuclease 1 (EXO1) is associated with increased levels of genomic instability in the telomere region, and this widespread genomic instability can promote cancer progression [43]. EXO1 is a therapeutic target of TNBC that serves an important role in the DDR by inhibiting the activity of PARP [44,45]. In our study, we found that the EXO1 gene has a positive correlation with eosinophils.…”

Screening of DNA Damage Repair Genes Involved in the Prognosis of Triple-Negative Breast Cancer Patients Based on Bioinformatics

“…Exonuclease 1 (EXO1) is associated with increased levels of genomic instability in the telomere region, and this widespread genomic instability can promote cancer progression ( Maciejowski and de Lange, 2017 ). EXO1 is a therapeutic target of TNBC that serves an important role in the DDR by inhibiting the activity of PARP ( Quist et al, 2019 ; Li et al, 2021 ). In our study, we found that the EXO1 gene has a positive correlation with eosinophils.…”

Identification of DNA Damage Repair-Associated Prognostic Biomarkers for Prostate Cancer Using Transcriptomic Data Analysis

“…It is noteworthy that EXO1 and EME2 are correlated with homologous recombination repair pathway in the functional annotation based on the Reactome database ( Figure 2 b). Several studies have reported that olaparib can inhibit the activity of EXO1 protein leading to inactivation of PARP enzymes [ 67 , 68 , 69 ], whereas there is currently no study that reports the direct interaction between PARP inhibitors and EME2 .…”