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Unraveling systemic responses to NQO1-activated IB-DNQ and Rucaparib single and dual agent therapy in triple-negative

Avery M Runnebohm1, H R Sagara Wijeratne1, Sarah A Peck Justice1,2

  • 1Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN.

Biorxiv : the Preprint Server for Biology
|May 27, 2024
PubMed

Insights

This study reveals how NQO1-activated drugs and Rucaparib synergistically kill triple-negative breast cancer (TNBC) cells by targeting DNA repair and cell cycle pathways. Multi-omics analysis uncovered key protein changes driving this cell death mechanism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Triple-negative breast cancer (TNBC) lacks common therapeutic targets, necessitating novel treatment strategies.
  • NQO1 is a promising target due to its high expression in TNBC and low expression in normal tissues.
  • Combining NQO1 bioactivatable drugs with PARP1 inhibitor Rucaparib shows synergistic cell death in TNBC.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying the synergistic efficacy of NQO1 bioactivatable drugs and Rucaparib in TNBC.
  • To investigate the impact of combination therapy on protein abundance, phosphorylation, and thermal stability.

Main Methods:

  • Global proteomics, phosphoproteomics, and thermal proteome profiling were employed.
  • Analysis focused on changes in protein expression, post-translational modifications, and protein stability.
  • Biophysical analyses assessed alterations in protein complex associations and interactions.

Main Results:

  • Combination treatment induced persistent DNA damage, evidenced by increased histone H2AX phosphorylation.
  • Thermal proteome profiling indicated H2AX destabilization, potentially linked to phosphorylation.
  • Kinase activity alterations in DNA repair and cell cycle pathways were predicted and observed.
  • Biophysical analysis revealed changes in SWI/SNF complex and tubulin/p53 interactions.

Conclusions:

  • The combination therapy targets DNA repair and cell cycle regulation, crucial cancer pathways.
  • The synergistic effect is dependent on NQO1 upregulation, selectively impacting cancer cells.
  • Multi-omics approaches are vital for understanding complex drug-induced cancer cell death mechanisms.
Keywords:
DNA damageIB-DNQRucaparibTriple negative breast cancercell cyclemass spectrometrymultiomicsphosphoproteomicstranscription

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