Related Experiment Video

Updated: Jun 28, 2025

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
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Activated NAD+ biosynthesis pathway induces olaparib resistance in BRCA1 knockout pancreatic cancer cells

Yuka Sasaki1,2, Takuma Inouchi1, Ryusuke Nakatsuka1

  • 1Department of Pharmacology, Faculty of Dentistry, Osaka Dental University, Hirakata, Osaka, Japan.

Plos One
|April 16, 2024
PubMed

Insights

PARP inhibitors are used to treat cancer, but resistance is a challenge. This study found that higher NAD+ levels in cancer cells contribute to resistance against PARP inhibitors like olaparib.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Poly (ADP-ribose) polymerase (PARP) inhibitors exploit synthetic lethality in homologous recombination deficient cancers.
  • Clinical resistance to PARP inhibitors, such as olaparib, is a significant challenge, and its mechanisms require further elucidation.

Purpose of the Study:

  • To investigate the mechanisms underlying acquired resistance to PARP inhibitors.
  • To identify molecular alterations associated with resistance in BRCA1-deficient pancreatic cancer cells.

Main Methods:

  • Established a BRCA1 knockout pancreatic cancer cell line (C1) and derived an olaparib-resistant subline (C1/OLA).
  • Performed RNA-sequencing and pathway analysis on C1 and C1/OLA cells treated with olaparib.
  • Assessed intracellular NAD+ levels and the effect of nicotinamide on PARP inhibitor sensitivity.

Main Results:

  • Olaparib-resistant cells (C1/OLA) exhibited an activated NAD+ metabolism pathway.
  • Increased expression of NAD+ biosynthetic enzymes (NAMPT, NMNAT2) and higher intracellular NAD+ levels were observed in resistant cells.
  • Elevated intracellular NAD+ levels conferred resistance to olaparib and talazoparib in sensitive cells.

Conclusions:

  • Upregulation of intracellular NAD+ metabolism is a key factor in the development of PARP inhibitor resistance.
  • Targeting NAD+ metabolism may represent a therapeutic strategy to overcome PARP inhibitor resistance in cancer.

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