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Dependence of tumor cell lines and patient-derived tumors on the NAD salvage pathway renders them sensitive to NAMPT inhibition with GNE-618.

ABSTRACT: Nicotinamide adenine dinucleotide (NAD) is a critical metabolite that is required for a range of cellular reactions. A key enzyme in the NAD salvage pathway is nicotinamide phosphoribosyl transferase (NAMPT), and here, we describe GNE-618, an NAMPT inhibitor that depletes NAD and induces cell death in vitro and in vivo. While cells proficient for nicotinic acid phosphoribosyl transferase (NAPRT1) can be protected from NAMPT inhibition as they convert nicotinic acid (NA) to NAD independent of the salvage pathway, this protection only occurs if NA is added before NAD depletion. We also demonstrate that tumor cells are unable to generate NAD by de novo synthesis as they lack expression of key enzymes in this pathway, thus providing a mechanistic rationale for the reliance of tumor cells on the NAD salvage pathway. Identifying tumors that are sensitive to NAMPT inhibition is one potential way to enhance the therapeutic effectiveness of an NAMPT inhibitor, and here, we show that NAMPT, but not NAPRT1, mRNA and protein levels inversely correlate with sensitivity to GNE-618 across a panel of 53 non-small cell lung carcinoma cell lines. Finally, we demonstrate that GNE-618 reduced tumor growth in a patient-derived model, which is thought to more closely represent heterogeneous primary patient tumors. Thus, we show that dependence of tumor cells on the NAD salvage pathway renders them sensitive to GNE-618 in vitro and in vivo, and our data support further evaluation of the use of NAMPT mRNA and protein levels as predictors of overall sensitivity.

SUBMITTER: Xiao Y

PROVIDER: S-EPMC3819631 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Dependence of tumor cell lines and patient-derived tumors on the NAD salvage pathway renders them sensitive to NAMPT inhibition with GNE-618.

Xiao Yang Y Elkins Kristi K Durieux Jenni K JK Lee Leslie L Oeh Jason J Yang Lulu X LX Liang Xiaorong X DelNagro Chris C Tremayne Jarrod J Kwong Mandy M Liederer Bianca M BM Jackson Peter K PK Belmont Lisa D LD Sampath Deepak D O'Brien Thomas T

Neoplasia (New York, N.Y.) 20131001 10

Nicotinamide adenine dinucleotide (NAD) is a critical metabolite that is required for a range of cellular reactions. A key enzyme in the NAD salvage pathway is nicotinamide phosphoribosyl transferase (NAMPT), and here, we describe GNE-618, an NAMPT inhibitor that depletes NAD and induces cell death in vitro and in vivo. While cells proficient for nicotinic acid phosphoribosyl transferase (NAPRT1) can be protected from NAMPT inhibition as they convert nicotinic acid (NA) to NAD independent of the ...[more]

PMID: 24204194

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Project description:Abstract BACKGROUND Current treatment of glioblastoma (GBM) with surgery and chemoRT yields an average survival of ~1.5 years, highlighting the need for more effective therapies. We have previously reported that PAK4 is a key modulator of radioresistance in GBM. Additionally, pathways that regulate differential energy metabolism in gliomas and circumvent tumor heterogeneity have recently emerged as promising therapeutic targets. We hypothesized that inhibition of NAMPT, the rate-limiting enzyme of the NAD+ salvage pathway, a key pathway preferentially used in glioma energy metabolism, would be effective against GBM. METHODS We tested the efficacy of KPT9274, a potent first-in-class dual inhibitor of PAK4 and NAMPT, currently in human trials against solid tumors and lymphomas (NCT02702492), on NAD levels and cell viability in glioma cell lines and patient-derived glioma stem-like cells (GSC). We also examined enzyme-kinetics of various components of the NAD salvage pathway and effects of NADH rescue by nicotinamide, NMN and NAD. Lastly, we examined the biological relevance of NAMPT inhibition in glioma cells and GSC using a combination of cell adhesion, wound-healing, transwell-migration and microtubule formation assays. RESULTS Treatment with KPT9274 resulted in potent depletion of NAD in glioma cells which was rescued by nicotinamide, NMN and NAD demonstrating its specificity against NAMPT. KPT-9274 treatment resulted in potent inhibition of cell adhesion, migration, cell invasion, endothelial tube formation and proliferation in glioma cells and GSC. In vivo studies in mouse bioluminescent intracranial glioma PDX model as well as PK studies are ongoing to confirm the pre-clinical significance of targeting NAMPT in gliomas and will be presented. CONCLUSIONS Our study demonstrates a key role for NAMPT in NAD generation in gliomas as seen by the potent biological effects of KPT-9274 against these tumors and supports the potential for targeting the NAD salvage pathway as a novel therapeutic strategy for treatment of GBM.

Dataset Information

Dependence of tumor cell lines and patient-derived tumors on the NAD salvage pathway renders them sensitive to NAMPT inhibition with GNE-618.

Publications

Dependence of tumor cell lines and patient-derived tumors on the NAD salvage pathway renders them sensitive to NAMPT inhibition with GNE-618.

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