NAMPT Inhibitor KPT-9274 Selectively Targets Self-Renewal Capacity in Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) is a heterogeneous disease that is characterized by an accumulation of neoplastic myeloid precursor cells in the bone marrow. Recently, multiple agents targeting AML associated mutations in FLT3, IDH1 and IDH2 have been developed. However, a majority of AML patients lack these mutations. Therefore, development of a novel therapeutic approach broadly relevant to AML would be attractive. The clonal capacity of AML cells is maintained by leukemic initiating cells (LICs), which possess self-renewal capabilities and are resistant against cytotoxic combination chemotherapy. Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step in the generation of NAD+, which is an important enzymatic cofactor and serves as a metabolite required for cellular respiration. LICs show a higher energy turnover rate than normal cells and are heavily reliant on oxidative phosphorylation. This suggests that energy generation processes, such as NAD+ biosynthesis, are critically required in myeloid malignancies. Thus, targeting the regeneration of NAD+ offers an attractive alternative therapeutic strategy in AML. Unlike many targeted therapies that are limited to one genetic subtype of AML, targeting regeneration of NAD+ via NAMPT inhibition could be relevant to a much broader patient population based upon metabolic differences between tumor and normal cells. We show that inhibition of NAMPT using the agent KPT-9274 induces loss of glycolytic and mitochondrial activity, more specifically a depleted total spare reserve capacity (p Disclosures Mims:Abbvie Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Novartis: Consultancy. Baloglu:Karyopharm Therpeutics: Employment. Senapedis:Karyopharm Therapeutics: Employment.