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

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...

Full description

Saved in:
Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2014-11, Vol.74 (21), p.5948-5954
Main Authors: Chan, Manuel, Gravel, Michel, Bramoullé, Alexandre, Bridon, Gaëlle, Avizonis, Daina, Shore, Gordon C, Roulston, Anne
Format: Article
Language:English
Subjects:
Animals
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - pathology
Cell Line, Tumor
Cytokines - antagonists & inhibitors
Cytokines - biosynthesis
DNA Repair - drug effects
Drug Synergism
Gene Expression Regulation, Neoplastic
Glutamates - administration & dosage
Guanidines - administration & dosage
Guanine - administration & dosage
Guanine - analogs & derivatives
Humans
Mice
NAD - metabolism
Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors
Nicotinamide Phosphoribosyltransferase - biosynthesis
Pemetrexed
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases - biosynthesis
Poly(ADP-ribose) Polymerases - genetics
Transcriptional Activation - genetics
Xenograft Model Antitumor Assays
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-14-0809