ArticlePloS one2024
Activated NAD+ biosynthesis pathway induces olaparib resistance in BRCA1 knockout pancreatic cancer cells.
Article in PloS one, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 3 citations in OpenAlex.
- Sensitizing Colorectal Cancer to PARP Inhibitors: Biomarkers, Mechanisms, and Combination Strategies.International journal of molecular sciences · 2026Review
- Role of Poly (ADP-Ribose) Polymerase-1 (PARP1) and Its Inhibitors for Cancer Therapy.Mini reviews in medicinal chemistry · 2026Review
- Mechanisms of Resistance to PARPi in Pancreatic Ductal Adenocarcinoma.Journal of cellular and molecular medicine · 2025Article
- All-trans Retinoic Acid Sensitizes Epithelial Ovarian Cancer to PARP Inhibition after Exposure to Cisplatin.Molecular cancer therapeutics · 2025Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
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Abstract
PARP inhibitors have been developed as anti-cancer agents based on synthetic lethality in homologous recombination deficient cancer cells. However, resistance to PARP inhibitors such as olaparib remains a problem in clinical use, and the mechanisms of resistance are not fully understood. To investigate mechanisms of PARP inhibitor resistance, we established a BRCA1 knockout clone derived from the pancreatic cancer MIA PaCa-2 cells, which we termed C1 cells, and subsequently isolated an olaparib-resistant C1/OLA cells. We then performed RNA-sequencing and pathway analysis on olaparib-treated C1 and C1/OLA cells. Our results revealed activation of cell signaling pathway related to NAD+ metabolism in the olaparib-resistant C1/OLA cells, with increased expression of genes encoding the NAD+ biosynthetic enzymes NAMPT and NMNAT2. Moreover, intracellular NAD+ levels were significantly higher in C1/OLA cells than in the non-olaparib-resistant C1 cells. Upregulation of intracellular NAD+ levels by the addition of nicotinamide also induced resistance to olaparib and talazoparib in C1 cells. Taken together, our findings suggest that upregulation of intracellular NAD+ is one of the factors underlying the acquisition of PARP inhibitor resistance.
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