Synthetic lethality of PARP and NAMPT inhibition in triple-negative breast cancer cells
Open accessAbstract
PARP inhibitors have been proposed as a potential targeted therapy for patients with triple-negative (ER-, PR-, HER2-negative) breast cancers. However, it is as yet unclear as to whether single agent or combination therapy using PARP inhibitors would be most beneficial. To better understand the mechanisms that determine the response to PARP inhibitors, we investigated whether enzymes involved in metabolism of the PARP substrate, β-NAD(+) , might alter the response to a clinical PARP inhibitor. Using an olaparib sensitization screen in a triple-negative (TN) breast cancer model, we identified nicotinamide phosphoribosyltransferase (NAMPT) as a non-redundant modifier of olaparib response. NAMPT is a rate-limiting enzyme involved in the generation of the PARP substrate β-NAD(+) and the suppression of β-NAD(+) levels by NAMPT inhibition most likely explains these observations. Importantly, the combination of a NAMPT small molecule inhibitor, FK866, with olaparib inhibited TN breast tumour growth in vivo to a greater extent than either single agent alone suggesting that assessing NAMPT/PARP inhibitor combinations for the treatment of TN breast cancer may be warranted.
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NAMPT inhibitors may be more effective in MYC-amplified glioblastoma or when combined with other drugs that deplete NAD+ pools.
“For example, NAMPT inhibitors may be more effective in contexts of MYC-amplified glioblastoma (Tateishi et al., 2016) or when used in combination with other drugs known to deplete NAD+ pools (Bajrami et al., 2012; Chan et al., 2014).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Bajrami et al., 2012
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- Authors
- Bajrami, I., Kigozi, A., Van Weverwijk, A., Brough, R., Frankum, J., Lord, C. J., & Ashworth, A.
- Affiliations
- Institute of Cancer Research (GB)
- Corresponding author
- Lord, Christopher J.
- Ashworth, Alan
- Venue
- EMBO Molecular Medicine
- Published
- 2012-08-30
- Volume
- 4
- Issue
- 10
- Pages
- 1087-1096
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC3491838
- OpenAlex
- W2137426380
- Cited by
- 136
- References
- 23
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 9 · 2023: 8 · 2022: 10 · 2021: 14 · 2020: 10 · 2019: 6 · 2018: 11 · 2017: 8 · 2016: 8 · 2015: 10 · 2014: 6 · 2013: 15
- FWCI
- 5.06
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EMBO Molecular Medicine (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Breakthrough Breast Cancer, Cancer Research UK
- AACR as part of the Stand Up to Cancer Breast Cancer Dream Team
- NHS
- Funded Access
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Keywords
- synthetic lethality, PARP inhibitors, visfatin, olaparib, triple-negative breast cancer, FK866, combination therapy
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Poly (ADP-Ribose) Polymerase-1, Acrylamides, Animals, Breast Neoplasms, Female, Humans, Mice, Nude, Phthalazines, Piperazines, Piperidines, Poly(ADP-ribose) Polymerases, Transplantation, Heterologous, Cytokines, Cell Line, Tumor, Mice, Nicotinamide Phosphoribosyltransferase
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