Identification of novel resistance mechanisms to NAMPT inhibition via the de novo NAD+ biosynthesis pathway and NAMPT mutation

Guo, Jun; Lam, Lloyd T.; Longenecker, K.L.; Bui, Mai H.; Idler, Kenneth B.; Glaser, Keith B.; Wilsbacher, Julie L.; Tse, Chris; Pappano, William N.; Huang, Tzu-Hsuan

doi:10.1016/j.bbrc.2017.07.143

Cited by 27 publications

(24 citation statements)

References 12 publications

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“…1a, c ) translated into a dependency on amino acids such as tryptophan and glutamine. Notably, a dependency on QPRT activity was recently observed in human fibrosarcoma cells with acquired resistant to NAMPT inhibition that still presented a point mutation in the NAMPT enzyme [ 29 ]. We specifically investigated tryptophan and glutamine for their role in acquired resistance to NAMPT inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, no cross-resistance to CHS-828 and FK866 was detected, suggesting that resistance to NAMPT inhibitors could be molecule-specific. Therefore, to date, tumor cell resistance to NAMPT inhibitors has been mostly ascribed to point mutations that are either proximal or distal to the enzyme substrate binding sites with the notable exception of one case of NAMPT inhibitor resistance, that was related to increased activity of the enzyme quinolinate phosphoribosyltransferase (QPRT), which mediates NAD + production from tryptophan [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Cancer cell metabolic plasticity allows resistance to NAMPT inhibition but invariably induces dependence on LDHA

et al. 2018

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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.Electronic supplementary materialThe online version of this article (10.1186/s40170-018-0174-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cancer cell metabolic plasticity allows resistance to NAMPT inhibition but invariably induces dependence on LDHA

et al. 2018

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“…Last, cross-resistance to a diverse set of NAMPT inhibitors has been already reported and demonstrated and therefore warrants for diverse inhibitors to be developed. Different mechanisms are responsible for resistance which include point mutation in the tunnel region, as well as increased expression of quinolate phosphoribosyltransferase an enzyme involved in the de novo NAD synthesis (Guo et al, 2017;Ogino et al, 2018).…”

Section: Recent Advances In the Medicinal Chemistry Of Intracellular mentioning

confidence: 99%

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

et al. 2020

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Nicotinamide adenine dinucleotide (NAD) is a cofactor of many enzymatic reactions as well as being a substrate for a number of NAD-consuming enzymes (e.g., PARPS, sirtuins, etc). NAD can be synthesized de novo starting from tryptophan, nicotinamide, nicotinic acid, or nicotinamide riboside from the diet. On the other hand, the nicotinamide that is liberated by NAD-consuming enzymes can be salvaged to reform NAD. In this former instance, nicotinamide phosphoribosyltransferase (NAMPT) is the bottleneck enzyme. In the many cells in which the salvage pathway is predominant, NAMPT, therefore, represents an important controller of intracellular NAD concentrations, and as a consequence of energy metabolism. It is, therefore, not surprising that NAMPT is over expressed by tumoral cells, which take advantage from this to sustain growth rate and tumor progression. This has led to the initiation of numerous medicinal chemistry programs to develop NAMPT inhibitors in the context of oncology. More recently, however, it has been shown that NAMPT inhibitors do not solely target the tumor but also have an effect on the immune system. To add complexity, this enzyme can also be secreted by cells, and in the extracellular space it acts as a cytokine mainly through the activation of Toll like Receptor 4 (TLR4), although it has not been clarified yet if this is the only receptor responsible for its actions. While specific small molecules have been developed only against the intracellular form of NAMPT, growing evidences sustain the possibility to target the extracellular form. In this contribution, the most recent evidences on the medicinal chemistry of NAMPT will be reviewed, together with the key elements that sustain the hypothesis of NAMPT targeting and the drawbacks so far encountered.

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“…Combinatorial targeting may have particular benefit when targeting NAMPT, especially because cancer cells can develop resistance to NAMPT inhibitors through enhancing NAD + de novo synthesis through upregulated quinolinic acid phosphoribosyltransferase (QAPRT), NAMPT mutations (Guo et al, 2017), or enhanced amino acid catabolism (such as tryptophan in de novo pathway and glutamine in salvage pathway) (Thongon et al, 2018).…”

Section: Targeting Nad + Biosynthetic Enzymesmentioning

confidence: 99%

Subcellular compartmentalization of NAD+ and its role in cancer: A sereNADe of metabolic melodies

Zhu

Liu

Park

et al. 2019

Pharmacology & Therapeutics

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Nicotinamide adenine dinucleotide (NAD +) is an essential biomolecule involved in many critical processes. Its role as both a driver of energy production and a signaling molecule underscores its importance in health and disease. NAD + signaling impacts multiple processes that are dysregulated in cancer, including DNA repair, cell proliferation, differentiation, redoxregulation, and oxidative stress. Distribution of NAD + is highly compartmentalized, with each subcellular NAD + pool differentially regulated and preferentially involved in distinct NAD +-dependent signaling or metabolic events. Emerging evidence suggests that targeting NAD + metabolism is likely to repress many specific mechanisms underlying tumor development and progression, including proliferation, survival, metabolic adaptations, invasive capabilities, heterotypic interactions with the tumor microenvironment, and stress response including notably DNA maintenance and repair. Here we provide a comprehensive overview of how compartmentalized NAD + metabolism in mitochondria, nucleus, cytosol, and extracellular space impacts cancer formation and progression, along with a discussion of the therapeutic potential of NAD +-targeting drugs in cancer.

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Identification of novel resistance mechanisms to NAMPT inhibition via the de novo NAD+ biosynthesis pathway and NAMPT mutation

Cited by 27 publications

References 12 publications

Cancer cell metabolic plasticity allows resistance to NAMPT inhibition but invariably induces dependence on LDHA

Cancer cell metabolic plasticity allows resistance to NAMPT inhibition but invariably induces dependence on LDHA

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

Subcellular compartmentalization of NAD+ and its role in cancer: A sereNADe of metabolic melodies

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