New Findings Reported from AbbVie Describe Advances in Biochemistry [Identification of novel resistance mechanisms to NAMPT inhibition via the de novo NAD(+) biosynthesis pathway and NAMPT mutation]
By a News Reporter-Staff News Editor at Cancer Weekly -- Investigators publish new report on Chemistry - Biochemistry. According to news reporting out of North Chicago, Illinois, by NewsRx editors, research stated, "Cancer cells have an unusually high requirement for the central and intermediary metabolite nicotinamide adenine dinucleotide (NAD(+)), and NAD(+) depletion ultimately results in cell death. The rate limiting step within the NAD(+) salvage pathway required for converting nicotinamide to NAD(+) is catalyzed by nicotinamide phosphoribosyltransferase (NAMPT)."
Our news journalists obtained a quote from the research from AbbVie, "Targeting NAMPT has been investigated as an anti-cancer strategy, and several highly selective small molecule inhibitors have been found to potently inhibit NAMPT in cancer cells, resulting in NAD(+) depletion and cytotoxicity. To identify mechanisms that could cause resistance to NAMPT inhibitor treatment, we generated a human fibrosarcoma cell line refractory to the highly potent and selective NAMPT small molecule inhibitor, GMX1778. We uncovered novel and unexpected mechanisms of resistance including significantly increased expression of quinolinate phosphoribosyl transferase (QPRT), a key enzyme in the de novo NAD(+) synthesis pathway. Additionally, exome sequencing of the NAMPT gene in the resistant cells identified a single heterozygous point mutation that was not present in the parental cell line. The combination of upregulation of the NAD(+) de novo synthesis pathway through QPRT over-expression and NAMPT mutation confers resistance to GMX1778, but the cells are only partially resistant to next-generation NAMPT inhibitors."
According to the news editors, the research concluded: "The resistance mechanisms uncovered herein provide a potential avenue to continue exploration of next generation NAMPT inhibitors to treat neoplasms in the clinic."
For more information on this research see: Identification of novel resistance mechanisms to NAMPT inhibition via the de novo NAD(+) biosynthesis pathway and NAMPT mutation. Biochemical and Biophysical Research Communications, 2017;491(3):681-686. Biochemical and Biophysical Research Communications can be contacted at: Academic Press Inc Elsevier Science, 525 B St, Ste 1900, San Diego, CA 92101-4495, USA. (Elsevier - www.elsevier.com; Biochemical and Biophysical Research Communications - www.journals.elsevier.com/biochemical-and-biophysical-research-communications/)
Our news journalists report that additional information may be obtained by contacting T.H. Huang, AbbVie Inc, North Chicago, IL 60064, United States. Additional authors for this research include L.T. Lam, K.L. Longenecker, M.H. Bui, K.B. Idler, K.B. Glaser, J.L. Wilsbacher, C. Tse, W.N. Pappano and J. Guo (see also Chemistry - Biochemistry).
Keywords for this news article include: North Chicago, Illinois, United States, North and Central America, Biochemistry, Chemistry, Oncology, Genetics, Cancer, AbbVie.
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