Synergy between the NAMPT inhibitor GMX1777(8) and pemetrexed in non-small cell lung cancer cells is mediated by PARP activation and enhanced NAD consumption

Chan, Manuel; Gravel, Michel; Bramoullé, Alexandre; Bridon, Gaëlle; Avizonis, Daina; Shore, Gordon C.; Roulston, Anne

doi:10.1158/0008-5472.can-14-0809

Cited by 46PARP inhibition in cancer therapySirtuins and Resveratrol in MedicineBiochemical and Molecular Research

Synergy between the NAMPT inhibitor GMX1777(8) and pemetrexed in non-small cell lung cancer cells is mediated by PARP activation and enhanced NAD consumption

Chan, Manuel, Gravel, Michel, Bramoullé, Alexandre, Bridon, Gaëlle, Avizonis, Daina, Shore, Gordon C., Roulston, Anne·2014·Cancer Research

DOI 10.1158/0008-5472.can-14-0809

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Abstract

GMX1778 and its prodrug GMX1777 represent a new class of cancer drugs that targets nicotinamide phosphoribosyltransferase (NAMPT) as a new strategy to interfere with biosynthesis of the key enzymatic cofactor NAD, which is critical for a number of cell functions, including DNA repair. Using a genome-wide synthetic lethal siRNA screen, we identified the folate pathway–related genes, deoxyuridine triphosphatase and dihydrofolate reductase, the silencing of which sensitized non–small cell lung carcinoma (NSCLC) cells to the cytotoxic effects of GMX. Pemetrexed is an inhibitor of dihydrofolate reductase currently used to treat patients with nonsquamous NSCLC. We found that combining pemetrexed with GMX1777 produced a synergistic therapeutic benefit in A549 and H1299 NSCLC cells in vitro and in a mouse A549 xenograft model of lung cancer. Pemetrexed is known to activate PARPs, thereby accelerating NAD consumption. Genetic or pharmacologic blockade of PARP activity inhibited this effect, impairing cell death by pemetrexed either alone or in combination with GMX1777. Conversely, inhibiting the base excision repair pathway accentuated NAD decline in response to GMX and the cytotoxicity of both agents either alone or in combination. These findings provide a mechanistic rationale for combining GMX1777 with pemetrexed as an effective new therapeutic strategy to treat nonsquamous NSCLC. Cancer Res; 74(21); 5948–54. ©2014 AACR.

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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 Chan et al., 2014

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Authors: Chan, M., Gravel, M., Bramoullé, A., Bridon, G., Avizonis, D., Shore, G. C., & Roulston, A.
Affiliations: McGill University (CA)
Institut du cancer Rosalind & Morris Goodman (CA)
Corresponding author: Roulston, Anne
ORCID: Bramoullé, Alexandre
Avizonis, Daina
Roulston, Anne
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2014-10-30
Volume: 74
Issue: 21
Pages: 5948-5954
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-14-0809
OpenAlex: W2100311133
Cited by: 46
References: 20
Citations by year: 2026: 1 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 8 · 2017: 4 · 2016: 7 · 2015: 5
FWCI: 2.57
Type: journal article
Language: en
Open access: closed
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
Funders: Canadian Institutes of Health Research (MOP#6192)
Topics: Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords: NAMPT inhibition, pemetrexed, non-small cell lung cancer, PARP activation, NAD+ consumption, base excision repair, dihydrofolate reductase, folate pathway, drug synergy, synthetic lethality, DNA repair, combination therapy
MeSH terms: Poly(ADP-ribose) Polymerase Inhibitors, Pemetrexed, Animals, Carcinoma, Non-Small-Cell Lung, DNA Repair, Drug Synergism, Glutamates, Guanidines, Guanine, Humans, NAD, Poly(ADP-ribose) Polymerases, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Cytokines, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Nicotinamide Phosphoribosyltransferase

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Synergy between the NAMPT inhibitor GMX1777(8) and pemetrexed in non-small cell lung cancer cells is mediated by PARP activation and enhanced NAD consumption

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