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Supplemental Figure S4 from Inhibition of NAD+-Dependent Metabolic Processes Induces Cellular Necrosis and Tumor Regression in Rhabdomyosarcoma Models

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posted on 2023-11-01, 07:20 authored by Grace B. McKay-Corkum, Victor J. Collins, Choh Yeung, Takeshi Ito, Sameer H. Issaq, David Holland, Ksenia Vulikh, Yiping Zhang, Unsun Lee, Haiyan Lei, Arnulfo Mendoza, Jack F. Shern, Marielle E. Yohe, Kazutoshi Yamamoto, Kelli Wilson, Jiuping Ji, Baktiar O. Karim, Craig J. Thomas, Murali C. Krishna, Leonard M. Neckers, Christine M. Heske

Supplemental Figure S4: Effect of OT-82 on mechanism of RMS cell death

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National Cancer Institute (NCI)

United States Department of Health and Human Services

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NIH Medical Research Scholars Program

Foundation for the NIH

Doris Duke Charitable Foundation (DDCF)

American Association for Dental Research

Colgate-Palmolive Company

Genentech

Elsevier

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ARTICLE ABSTRACT

Deregulated metabolism in cancer cells represents a vulnerability that may be therapeutically exploited to benefit patients. One such target is nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage pathway. NAMPT is necessary for efficient NAD+ production and may be exploited in cells with increased metabolic demands. We have identified NAMPT as a dependency in rhabdomyosarcoma (RMS), a malignancy for which novel therapies are critically needed. Here we describe the effect of NAMPT inhibition on RMS proliferation and metabolism in vitro and in vivo. Assays of proliferation and cell death were used to determine the effects of pharmacologic NAMPT inhibition in a panel of ten molecularly diverse RMS cell lines. Mechanism of the clinical NAMPTi OT-82 was determined using measures of NAD+ and downstream NAD+-dependent functions, including energy metabolism. We used orthotopic xenograft models to examine tolerability, efficacy, and drug mechanism in vivo. Across all ten RMS cell lines, OT-82 depleted NAD+ and inhibited cell growth at concentrations ≤1 nmol/L. Significant impairment of glycolysis was a universal finding, with some cell lines also exhibiting diminished oxidative phosphorylation. Most cell lines experienced profound depletion of ATP with subsequent irreversible necrotic cell death. Importantly, loss of NAD and glycolytic activity were confirmed in orthotopic in vivo models, which exhibited complete tumor regressions with OT-82 treatment delivered on the clinical schedule. RMS is highly vulnerable to NAMPT inhibition. These findings underscore the need for further clinical study of this class of agents for this malignancy.

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