FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2495353249> ?p ?o ?g. }

• W2495353249 abstract "Targeting NAD(H) metabolism is being interrogated as a novel anti-cancer strategy. Nicotinamide phoshophoribosyltransferase (NAMPT) was found to be overexpressed in tumor cells, and plays a key role in the replenishment of the NAD(H) pool in cells. In this study we have used a commercially available NAMPT inhibitor, GMX1778, which exerts a cytotoxic effect by decreasing the cellular level of NAD(H). Through serial selection with increasing sub-lethal concentrations of GMX1778, we derived a GMX1778-resistant HT1080 human fibrosarcoma cell line (HT1080-GMX). The IC50 value for GMX1778-induced cell killing of the resistant cell line was 100-fold greater than that determined for the parental cell line. No significant change in the level of expression of NAMPT was observed in HT1080 vs. HT1080-GMX cells. However, a key enzyme in the de novo NAD(H) synthesis pathway known as quinolinate phosphoribosyl transferase (QPRT) was significantly upregulated as validated by Western blot and bDNA analysis. Knockdown of QPRT partially restored the sensitivity to GMX1778 exposure in HT1080-GMX cells, but did not affect the parental cells. The cytotoxicity of GMX1778 can be partially rescued with exogenous quinolinic acid, which permits NAD(H) repletion via QPRT in the de novo pathway, in HT1080-GMX cells but not HT1080 parental cells. Overexpression of QPRT in HT1080 cells did not fully rescue GMX-induced cytotoxicity and strongly suggests that there are additional mechanisms of resistance in the HT1080-GMX cell line beyond QPRT overexpression. Exome sequencing of the NAMPT gene in the HT1080-GMX resistant lines identified a single mutation of amino acid residue 18 from tyrosine to cysteine [NAMPT(Y18C)] located in the first exon of one allele. Tyrosine 18 is located near the active site of NAMPT and associates with NAMPT small molecule inhibitors through a pi stacking interaction, as determined by studies of the enzyme9s crystal structure. Overexpression of the NAMPT mutant Y18C in HT1080 cells significantly reduced the sensitivity to GMX1778 exposure, but overexpression of a NAMPT Y18F mutant had no effects compared to the parental line. Based on our results, activation of an alternate NAD(H) biosynthesis pathway via QPRT or the Y18C mutation within the NAMPT coding sequence can both be contributors to resistance in this line. The characterization of resistance inducing up-regulation of other sources of NAD(H) such as de novo synthesis or mutations in NAMPT may be useful in developing next-generation NAMPT inhibitors that are less affected by known resistance mechanisms. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: jun guo, Chris Tse, William N. Pappano. Identification of a novel NAMPT inhibition resistance mechanism utilizing the de novo NAD+ biosynthesis pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2127." @default.
• W2495353249 created "2016-08-23" @default.
• W2495353249 creator A5010630631 @default.
• W2495353249 creator A5045470360 @default.
• W2495353249 creator A5075972413 @default.
• W2495353249 date "2016-07-15" @default.
• W2495353249 modified "2023-09-22" @default.
• W2495353249 title "Abstract 2127: Identification of a novel NAMPT inhibition resistance mechanism utilizing the de novo NAD+ biosynthesis pathway" @default.
• W2495353249 doi "https://doi.org/10.1158/1538-7445.am2016-2127" @default.
• W2495353249 hasPublicationYear "2016" @default.
• W2495353249 type Work @default.
• W2495353249 sameAs 2495353249 @default.
• W2495353249 citedByCount "0" @default.
• W2495353249 crossrefType "proceedings-article" @default.
• W2495353249 hasAuthorship W2495353249A5010630631 @default.
• W2495353249 hasAuthorship W2495353249A5045470360 @default.
• W2495353249 hasAuthorship W2495353249A5075972413 @default.
• W2495353249 hasConcept C109316439 @default.
• W2495353249 hasConcept C1491633281 @default.
• W2495353249 hasConcept C153911025 @default.
• W2495353249 hasConcept C173396325 @default.
• W2495353249 hasConcept C181199279 @default.
• W2495353249 hasConcept C202751555 @default.
• W2495353249 hasConcept C2776495794 @default.
• W2495353249 hasConcept C2777751087 @default.
• W2495353249 hasConcept C2780391879 @default.
• W2495353249 hasConcept C502942594 @default.
• W2495353249 hasConcept C54009773 @default.
• W2495353249 hasConcept C54355233 @default.
• W2495353249 hasConcept C55493867 @default.
• W2495353249 hasConcept C75520062 @default.
• W2495353249 hasConcept C81885089 @default.
• W2495353249 hasConcept C86803240 @default.
• W2495353249 hasConceptScore W2495353249C109316439 @default.
• W2495353249 hasConceptScore W2495353249C1491633281 @default.
• W2495353249 hasConceptScore W2495353249C153911025 @default.
• W2495353249 hasConceptScore W2495353249C173396325 @default.
• W2495353249 hasConceptScore W2495353249C181199279 @default.
• W2495353249 hasConceptScore W2495353249C202751555 @default.
• W2495353249 hasConceptScore W2495353249C2776495794 @default.
• W2495353249 hasConceptScore W2495353249C2777751087 @default.
• W2495353249 hasConceptScore W2495353249C2780391879 @default.
• W2495353249 hasConceptScore W2495353249C502942594 @default.
• W2495353249 hasConceptScore W2495353249C54009773 @default.
• W2495353249 hasConceptScore W2495353249C54355233 @default.
• W2495353249 hasConceptScore W2495353249C55493867 @default.
• W2495353249 hasConceptScore W2495353249C75520062 @default.
• W2495353249 hasConceptScore W2495353249C81885089 @default.
• W2495353249 hasConceptScore W2495353249C86803240 @default.
• W2495353249 hasLocation W24953532491 @default.
• W2495353249 hasOpenAccess W2495353249 @default.
• W2495353249 hasPrimaryLocation W24953532491 @default.
• W2495353249 hasRelatedWork W1486973429 @default.
• W2495353249 hasRelatedWork W2041163347 @default.
• W2495353249 hasRelatedWork W2054739542 @default.
• W2495353249 hasRelatedWork W2090156221 @default.
• W2495353249 hasRelatedWork W2315816673 @default.
• W2495353249 hasRelatedWork W2331964198 @default.
• W2495353249 hasRelatedWork W2403684948 @default.
• W2495353249 hasRelatedWork W2416334542 @default.
• W2495353249 hasRelatedWork W2416711198 @default.
• W2495353249 hasRelatedWork W2480049046 @default.
• W2495353249 hasRelatedWork W2494900292 @default.
• W2495353249 hasRelatedWork W2503576709 @default.
• W2495353249 hasRelatedWork W2561074847 @default.
• W2495353249 hasRelatedWork W2584576127 @default.
• W2495353249 hasRelatedWork W2753962236 @default.
• W2495353249 hasRelatedWork W2795126336 @default.
• W2495353249 hasRelatedWork W2808428507 @default.
• W2495353249 hasRelatedWork W2887961399 @default.
• W2495353249 hasRelatedWork W3083914738 @default.
• W2495353249 hasRelatedWork W3096590361 @default.
• W2495353249 isParatext "false" @default.
• W2495353249 isRetracted "false" @default.
• W2495353249 magId "2495353249" @default.
• W2495353249 workType "article" @default.