Loss of NAPRT1 Expression by Tumor-Specific Promoter Methylation Provides a Novel Predictive Biomarker for NAMPT Inhibitors

Shames, David S.; Elkins, Kristi; Walter, Kimberly; Holcomb, Thomas; Du, Pan; Mohl, Dane; Xiao, Yang; Pham, Thinh Q.; Haverty, Peter M.; Liederer, Bianca M.; Liang, Xiaorong; Yauch, Robert L.; O’Brien, Tom; Bourgon, Richard; Koeppen, Hartmut; Belmont, Lisa D.

doi:10.1158/1078-0432.ccr-13-1186

Cited by 70 publications

(74 citation statements)

References 33 publications

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“…In cancer cells, low Naprt1 expression may be mediated by NAPRT1 promoter methylation (Shames et al, 2013). In keeping with these prior findings, we found that the NAPRT1 promoter CpG island was hypermethylated in our cell lines with very low Naprt1 expression, including all IDH1 mutant lines (Figure 4K).…”

Section: Resultsmentioning

confidence: 99%

Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion

et al. 2015

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Summary Heterozygous mutation of IDH1 in cancers modifies IDH1 enzymatic activity, reprogramming metabolite flux and markedly elevating 2-hydroxyglutarate (2-HG). Here, we found that 2-HG depletion did not inhibit growth of several IDH1 mutant solid cancer types. To identify other metabolic therapeutic targets, we systematically profiled metabolites in endogenous IDH1 mutant cancer cells after mutant IDH1 inhibition and discovered a profound vulnerability to depletion of the coenzyme NAD+. Mutant IDH1 lowered NAD+ levels by downregulating the NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (Naprt1), sensitizing to NAD+ depletion via concomitant nicotinamide phosphoribosyltransferase (NAMPT) inhibition. NAD+ depletion activated the intracellular energy sensor AMPK, triggered autophagy and resulted in cytotoxicity. Thus, we identify NAD+ depletion as a metabolic susceptibility of IDH1 mutant cancers.

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Section: Resultsmentioning

confidence: 99%

Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion

et al. 2015

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“…Because Myc has been reported to induce NAMPT expression (35) and Naprt1 expression is known to modulate sensitivity to NAMPT inhibitors (36, 37), we evaluated the expression of Naprt1 as well as NAMPT in our GBM tumorsphere lines. We found that NAMPT expression was similar in all GBM tumorsphere lines tested (Fig.…”

Section: Resultsmentioning

confidence: 99%

Myc-Driven Glycolysis Is a Therapeutic Target in Glioblastoma

Tateishi

Iafrate

et al. 2016

Clinical Cancer Research

121

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PURPOSE Deregulated Myc drives an oncogenic metabolic state, including pseudohypoxic glycolysis, adapted for the constitutive production of biomolecular precursors to feed rapid tumor cell growth. In glioblastoma (GBM), Myc facilitates renewal of the tumor initiating cell reservoir contributing to tumor maintenance. We investigated whether targeting the Myc-driven metabolic state could be a selectively toxic therapeutic strategy for GBM. METHODS The glycolytic dependency of Myc-driven GBM was tested using 13C metabolic flux analysis, glucose-limiting culture assays and glycolysis inhibitors, including inhibitors of the NAD+ salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in MYC and MYCN shRNA knockdown and lentivirus overexpression systems and in patient-derived GBM tumorspheres with and without MYC/MYCN amplification. The in vivo efficacy of glycolyic inhibition was tested using NAMPT inhibitors in MYCN amplified patient-derived GBM orthotopic xenograft mouse models. RESULTS Enforced Myc overexpression increased glucose flux and expression of glycolytic enzymes in GBM cells. Myc and N-Myc knockdown and Myc overexpression systems demonstrated that Myc activity determined sensitivity and resistance to inhibition of glycolysis. Small molecule inhibitors of glycolysis, particularly NAMPT inhibitors, were selectively toxic to MYC/MYCN amplified patient-derived GBM tumorspheres. NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing MYCN amplified patient-derived GBM orthotopic xenografts. CONCLUSION Myc activation in GBM generates a dependency on glycolysis and an addiction to metabolites required for glycolysis. Glycolytic inhibition via NAMPT inhibition represents a novel metabolically-targeted therapeutic strategy for MYC or MYCN amplified GBM and potentially other cancers genetically driven by Myc.

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“…Studies suggest that select tumor types are "addicted" to the NAMPT-dependent salvage pathway due to the downregulation of alternative NAD 1 production pathways and are therefore more sensitive to NAMPT inhibition. 17,18 Several NAD 1 consumer proteins, such as CD38, poly (ADP-ribose) polymerase, and sirtuins, have been shown to manage DNA repair mechanisms and mediate cancer disease progression by protecting cells during nutrient-deficient events. [19][20][21][22][23][24] In the absence of NAD 1 , both classes of proteins lose their cytotoxic protective features, making NAD 1 reduction a potential target for cancer therapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia

Mitchell¹,

Larkin²,

Grieselhuber³

et al. 2019

Blood Advances

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Key Points• KPT-9274, via its protein target NAMPT, diminishes NAD 1 levels and cellular respiration, leading to cell death.• Orally bioavailable KPT-9274 exhibits targetspecific activity in cell lines and patientderived xenograft models of AML. Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD 1 and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD 1 , whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML.Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.

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Loss of NAPRT1 Expression by Tumor-Specific Promoter Methylation Provides a Novel Predictive Biomarker for NAMPT Inhibitors

Cited by 70 publications

References 33 publications

Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion

Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion

Myc-Driven Glycolysis Is a Therapeutic Target in Glioblastoma

Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia

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