title: Supplementation of nicotinic acid with NAMPT inhibitors results in loss of in vivo efficacy in NAPRT1-deficient tumor models.
abstract: Nicotinamide adenine dinucleotide (NAD) is a metabolite essential for cell survival and generated de novo from tryptophan or recycled from nicotinamide (NAM) through the nicotinamide phosphoribosyltransferase (NAMPT)-dependent salvage pathway. Alternatively, nicotinic acid (NA) is metabolized to NAD through the nicotinic acid phosphoribosyltransferase domain containing 1 (NAPRT1)-dependent salvage pathway. Tumor cells are more reliant on the NAMPT salvage pathway making this enzyme an attractive therapeutic target. Moreover, the therapeutic index of NAMPT inhibitors may be increased by in NAPRT-deficient tumors by NA supplementation as normal tissues may regenerate NAD through NAPRT1. To confirm the latter, we tested novel NAMPT inhibitors, GNE-617 and GNE-618, in cell culture- and patient-derived tumor models. While NA did not protect NAPRT1-deficient tumor cell lines from NAMPT inhibition in vitro, it rescued efficacy of GNE-617 and GNE-618 in cell culture- and patient-derived tumor xenografts in vivo. NA co-treatment increased NAD and NAM levels in NAPRT1-deficient tumors to levels that sustained growth in vivo. Furthermore, NAM co-administration with GNE-617 led to increased tumor NAD levels and rescued in vivo efficacy as well. Importantly, tumor xenografts remained NAPRT1-deficient in the presence of NA, indicating that the NAPRT1-dependent pathway is not reactivated. Protection of NAPRT1-deficient tumors in vivo may be due to increased circulating levels of metabolites generated by mouse liver, in response to NA or through competitive reactivation of NAMPT by NAM. Our results have important implications for the development of NAMPT inhibitors when considering NA co-treatment as a rescue strategy.
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, CA.
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Brien
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, CA.
authors.forename: Jason
authors.initials: J
authors.lastname: Oeh
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, CA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Biomedical Imaging, Genentech, South San Francisco, CA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Vanderbilt
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA.
authors.forename: Ann
authors.initials: A
authors.lastname: Qin
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA.
authors.forename: Lulu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, CA.
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Lee
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA.
authors.forename: Justin
authors.initials: J
authors.lastname: Ly
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, CA.
authors.forename: Ely
authors.initials: E
authors.lastname: Cosino
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, CA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: LaCap
authors.affiliation: Department of Biomedical Imaging, Genentech, South San Francisco, CA.
authors.forename: Annie
authors.initials: A
authors.lastname: Ogasawara
authors.affiliation: Department of Biomedical Imaging, Genentech, South San Francisco, CA.
authors.forename: Simon
authors.initials: S
authors.lastname: Williams
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, CA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Nannini
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA.
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
authors.affiliation: Department of Discovery Oncology, Genentech, South San Francisco, CA.
authors.forename: Peter
authors.initials: P
authors.lastname: Jackson
authors.affiliation: Department of Discovery Chemistry, Genentech, South San Francisco, CA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.affiliation: Department of Translational Oncology, Genentech, South San Francisco, CA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009243:NAD / Q000378:metabolism; D009525:Niacin / Q000008:administration & dosage; D009536:Niacinamide / Q000008:administration & dosage; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010430:Pentosyltransferases / Q000172:deficiency* / Q000235:genetics; D013450:Sulfones / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; C000591022:GNE-617; D006574:Heterocyclic Compounds, 2-Ring; D013450:Sulfones; D009243:NAD; D009536:Niacinamide; D009525:Niacin; D010430:Pentosyltransferases; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C021864:nicotinate phosphoribosyltransferase