Distinct Capabilities in NAD Metabolism Mediate Resistance to NAMPT Inhibition in Glioblastoma.

Simple Summary: Patients with glioblastoma have very few treatment options; even with best treatment, including surgery, radiotherapy and chemotherapy, overall survival time is poor. Cancer cells need very high levels of energy to maintain their rapid growth, and a key component of this is a chemical called NAD. We can block the production of NAD in cancer cells by using inhibitors of specific substances in cells, limiting the growth of the tumour. This study highlights how cancer cells might exhibit resistance to inhibitors of NAD production, and how we can select a subset of patients that are uniquely responsive to these types of inhibitors. Furthermore, this study demonstrates that these inhibitors improve the effectiveness of the type of chemotherapy most often used to treat patients with aggressive brain tumours, called temozolomide. Patients may therefore benefit from the use of inhibitors of NAD production in combination with temozolomide. Glioblastoma (GBM) cells require high levels of nicotinamide adenine dinucleotide (NAD) to fuel metabolic reactions, regulate their cell cycle and support DNA repair in response to chemotherapy and radiation. Inhibition of a key enzyme in NAD biosynthesis, NAMPT, has demonstrated significant anti-neoplastic activity. Here, we sought to characterise NAD biosynthetic pathways in GBM to determine resistance mechanisms to NAD inhibitors. GBM cells were treated with the NAMPT inhibitor FK866 with and without NAD precursors, and were analysed by qPCR, Western blot and proliferation assays (monolayer and spheroid). We also measured changes in the cell cycle, apoptosis, NAD/NADH levels and energy production. We performed orthoptic xenograft experiments in athymic nude mice to test the efficacy of FK866 in combination with temozolomide (TMZ). We show that the expression of key genes involved in NAD biosynthesis is highly variable across GBM tumours. FK866 inhibits proliferation, reduces NAD levels and limits oxidative metabolism, leading to G2/M cell cycle arrest; however, this can be reversed by supplementation with specific NAD precursors. Furthermore, FK866 potentiates the effects of radiation and TMZ in vitro and in vivo. NAMPT inhibitors should be considered for the treatment of GBM, with patients stratified based on their expression of key enzymes in other NAD biosynthetic pathways. [ABSTRACT FROM AUTHOR]

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