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Updated: Jun 13, 2025

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
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Synergistic Effect of Ubiquitin-Specific Protease 14 and Poly(ADP-Ribose) Glycohydrolase Co-Inhibition in

Pisong Li1, Xiaoyu Zhu1, Hui Qu1

  • 1Department of Breast and Thyroid Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, People's Republic of China.

Oncotargets and Therapy
|September 11, 2024
PubMed
Abstract

Insights

This study shows that combining PARG inhibitor COH34 with USP14 inhibitor IU1-248 can overcome PARP inhibitor resistance in BRCA-mutant triple-negative breast cancer (TNBC). This combination offers a potential new treatment strategy for resistant TNBC tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Poly(ADP-ribose) polymerase (PARP) inhibitors show limited clinical benefit in triple-negative breast cancer (TNBC) due to resistance.
  • BRCA-mutant TNBC requires alternative treatment strategies beyond PARP inhibition.
  • Poly(ADP-ribose) glycohydrolase (PARG) and ubiquitin-specific protease (USP) 14 are involved in DNA repair pathways.

Purpose of the Study:

  • To investigate the synergistic lethal effect of PARG inhibitor COH34 and USP14 inhibitor IU1-248 in BRCA1-mutant, PARP inhibitor-resistant TNBC cells.
  • To elucidate the underlying molecular mechanisms of this combined therapeutic approach.

Main Methods:

  • Cytotoxicity was assessed using cell viability, proliferation assays, and flow cytometry in HCC1937 and SUM149PT TNBC cell lines.
  • Molecular mechanisms were explored via immunofluorescence staining, DNA repair reporter assays, and Western blot analysis.

Main Results:

  • The combination of IU1-248 and COH34 demonstrated synergistic cytotoxicity against BRCA-mutant TNBC cells, outperforming PARG inhibition alone.
  • IU1-248-mediated USP14 inhibition increased DNA damage and promoted non-homologous end joining (NHEJ) repair.
  • Inhibition of NHEJ attenuated the synergistic effects, indicating its crucial role in the observed outcome.
  • IU1-248 promoted NHEJ repair by downregulating c-Myc expression.

Conclusions:

  • The combination of PARG and USP14 inhibitors presents a promising strategy to overcome PARP inhibitor resistance in BRCA-mutant TNBC.
  • USP14 inhibition could expand the therapeutic utility of PARG inhibitors in resistant TNBC settings.
Keywords:
BRCANHEJPARGUSP14c-Myctriple-negative breast cancer

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