title: 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.
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.
authors.affiliation: Laboratory for Therapeutic Development, McGill University, Montreal, Québec, Canada.
authors.forename: Manuel
authors.initials: M
authors.lastname: Chan
authors.affiliation: Laboratory for Therapeutic Development, McGill University, Montreal, Québec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Gravel
authors.affiliation: Laboratory for Therapeutic Development, McGill University, Montreal, Québec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bramoullé
authors.affiliation: Metabolomics Core Facility, Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Québec, Canada. Department of Biochemistry, McGill University, Montreal, Québec Canada.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Bridon
authors.affiliation: Metabolomics Core Facility, Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Québec, Canada. Department of Biochemistry, McGill University, Montreal, Québec Canada.
authors.forename: Daina
authors.initials: D
authors.lastname: Avizonis
authors.affiliation: Laboratory for Therapeutic Development, McGill University, Montreal, Québec, Canada.
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Shore
authors.affiliation: Laboratory for Therapeutic Development, McGill University, Montreal, Québec, Canada. anne.roulston@mcgill.ca.
authors.forename: Anne
authors.initials: A
authors.lastname: Roulston
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004260:DNA Repair / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D005971:Glutamates / Q000008:administration & dosage*; D006146:Guanidines / Q000008:administration & dosage*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D051379:Mice; D009243:NAD / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000068437:Pemetrexed; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C541789:1-(2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxycarbonyloxymethyl)-4-(N'-cyano-N''-(6-(4-chlorophenoxy)hexyl)-N-guanidino)pyridinium; D016207:Cytokines; D005971:Glutamates; D006146:Guanidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000068437:Pemetrexed; D009243:NAD; D006147:Guanine; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D011065:Poly(ADP-ribose) Polymerases