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Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
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BKM120 sensitizes BRCA-proficient triple negative breast cancer cells to olaparib through regulating FOXM1 and Exo1

Yu Li1, Yuantao Wang2, Wanpeng Zhang2

  • 1State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, P. R. China.

Scientific Reports
|February 27, 2021
PubMed

Insights

Dual inhibition of Phosphoinositide 3-kinase (PI3K) and Poly (ADP-ribose) polymerase (PARP) effectively targets triple-negative breast cancer (TNBC) by impairing DNA repair mechanisms. This approach broadens PARP inhibitor applications to BRCA-proficient TNBC.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Poly (ADP-ribose) polymerase (PARP) inhibitors show efficacy in BRCA-mutated triple-negative breast cancer (TNBC).
  • Broader application of PARP inhibitors is limited by their narrow clinical indication.
  • Phosphoinositide 3-kinase (PI3K) inhibition can sensitize BRCA-proficient TNBC to PARP inhibitors, but the underlying mechanisms require elucidation.

Purpose of the Study:

  • To investigate the mechanism of synergistic effects of dual PI3K and PARP inhibition in DNA damage response in TNBC.
  • To explore the impact on DNA single-strand break (SSB) and double-strand break (DSB) repair pathways.
  • To identify novel therapeutic targets for TNBC treatment.

Main Methods:

  • Utilized dual PI3K and PARP inhibition with BKM120 and olaparib on BRCA-proficient TNBC cell lines (MDA-MB-231 and MDA231-LM2).
  • Assessed effects on cell proliferation, reactive oxygen species (ROS) production, DNA damage, and expression of key DNA repair proteins (PARP1/2, BRCA1/2, Rad51/52, FOXM1, Exo1).
  • Investigated involvement of PI3K/Akt/NFκB/c-Myc and PI3K/Akt/FOXM1/Exo1 signaling pathways.

Main Results:

  • Dual PI3K and PARP inhibition significantly reduced proliferation in BRCA-proficient TNBC cell lines.
  • BKM120 induced oxidative DNA damage and downregulated PARP1/2 expression, impairing SSB repair.
  • BKM120 inhibited BRCA1/2 and Rad51/52 expression via PI3K/Akt/NFκB/c-Myc and PI3K/Akt/FOXM1/Exo1 pathways, hindering DSB repair and inducing homologous recombination deficiency (HRD).

Conclusions:

  • Dual PI3K and PARP inhibition effectively impairs both SSB and DSB repair in TNBC.
  • PI3K inhibition induces HRD, expanding the therapeutic potential of PARP inhibitors like olaparib to HR-proficient TNBC.
  • FOXM1 and Exo1 represent novel therapeutic targets in DNA damage response pathways for TNBC treatment.

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