Abstract
BackgroundInhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. However, continuous exposure to NAMPT inhibitors, such as FK866, can induce acquired resistance.MethodsWe developed FK866-resistant CCRF-CEM (T cell acute lymphoblastic leukemia) and MDA MB231 (breast cancer) models, and by exploiting an integrated approach based on genetic, biochemical, and genome wide analyses, we annotated the drug resistance mechanisms.ResultsAcquired resistance to FK866 was independent of NAMPT mutations but rather was based on a shift towards a glycolytic metabolism and on lactate dehydrogenase A (LDHA) activity. In addition, resistant CCRF-CEM cells, which exhibit high quinolinate phosphoribosyltransferase (QPRT) activity, also exploited amino acid catabolism as an alternative source for NAD+ production, becoming addicted to tryptophan and glutamine and sensitive to treatment with the amino acid transport inhibitor JPH203 and with l-asparaginase, which affects glutamine exploitation. Vice versa, in line with their low QPRT expression, FK866-resistant MDA MB231 did not rely on amino acids for their resistance phenotype.ConclusionsOur study identifies novel mechanisms of resistance to NAMPT inhibition, which may be useful to design more rational strategies for targeting cancer metabolism.
Highlights
Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models
Generation of FK866-resistant cancer cell models The absence of nicotinic acid phosphoribosyltransferase (NAPRT) in CCRF-CEM (CEM) cells and the low expression of quinolinate phosphoribosyltransferase (QPRT) in MDA MB231 (MDA) cells were found to be the main differences between the two cell lines with respect to their NAD+ production apparatus (Fig. 1b–d)
Targeting lactate dehydrogenase A (LDHA) together with NAMPT may offer novel opportunities for selective killing of cancer cells, in cancer types that are addicted to aerobic glycolysis for survival
Summary
Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. The development of drug resistance during chemo- or targeted-therapies is a common event, which typically underlies disease relapse and is frequently associated with a poor prognosis. The molecular mechanisms responsible for drug resistance vary depending on the agent used, but some common mechanisms frequently do come into play [2]. NAMPT has been proposed as a viable cancer drug target, and many molecular agents have been developed that inhibit its enzymatic function, such as FK866, GNE618, and CHS-828 [13, 14].
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